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United States Patent |
5,719,278
|
Albright
,   et al.
|
February 17, 1998
|
Tricyclic benzazepine vasopressin antagonists
Abstract
Tricyclic compound of the general Formula I:
##STR1##
as defined herein which exhibit antagonist activity at V.sub.1 and/or
V.sub.2 receptors and exhibit in vivo vasopressin antagonist activity,
methods for using such compounds in treating diseases characterized by
excess renal reabsorption of water, and process for preparing such
compounds.
Inventors:
|
Albright; Jay D. (Nanuet, NY);
Santos; Efren G. Delos (Nanuet, NY);
Du; Xuemei (Valley Cottage, NY);
Reich; Marvin F. (Suffern, NY)
|
Assignee:
|
American Cyanamid Company (Madison, NJ)
|
Appl. No.:
|
657830 |
Filed:
|
May 31, 1996 |
Current U.S. Class: |
540/578; 540/542 |
Intern'l Class: |
C07D 491/147; C07D 498/14; A61K 031/55 |
Field of Search: |
540/542,578
514/81,215
|
References Cited
U.S. Patent Documents
4766108 | Aug., 1988 | Ali | 514/16.
|
5055448 | Oct., 1991 | Manning et al. | 514/16.
|
5070187 | Dec., 1991 | Gavras et al. | 530/315.
|
5258510 | Nov., 1993 | Ogawa et al. | 540/476.
|
5532235 | Jul., 1996 | Albright et al. | 514/215.
|
Foreign Patent Documents |
0382185 | Feb., 1990 | EP.
| |
0470514 | Aug., 1991 | EP.
| |
0514667 | Apr., 1992 | EP.
| |
0533242 | Sep., 1992 | EP.
| |
0533240 | Sep., 1992 | EP.
| |
0533243 | Sep., 1992 | EP.
| |
0533244 | Sep., 1992 | EP.
| |
0620216 | Apr., 1994 | EP.
| |
9105549 | May., 1991 | JP.
| |
9404525 | Mar., 1994 | JP.
| |
9414796 | Jul., 1994 | JP.
| |
9420473 | Sep., 1994 | JP.
| |
9412476 | Sep., 1994 | JP.
| |
Other References
J. Med. Chem., 1992,35, 3905-3918, Williams et al.
J. Med. Chem., 1992, 35, 3895-3904-Manning et al.
J. Med. Chem. 1992, 35, 382-388, Manning et al.
From Vasopressin Antagonist to Agonist, DN -31 P (4), May 1991, Ruffolo et
al.
Br. J. Pharmacol. (1992), 105, 787-791, Yamamura et al.
Science, vol. 252, pp. 572-574, Yamamura et al. (1991).
J. Med. Chem., 1992 35, 3919-3927, Evans et al.
J. Med. Chem., 1993, 36, 3993-4005, Evans et al.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Wong; King Lit
Attorney, Agent or Firm: Eck; Steven R.
Parent Case Text
CONTROL REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application Serial No.
373,139, filed Jan. 17, 1995, now U.S. Pat. No. 5,532,235.
Claims
What is claimed is:
1. A compound selected from Formula I:
##STR134##
wherein: the moiety:
##STR135##
represents an unsaturated 6-membered heterocyclic aromatic ring containing
one nitrogen atom optionally substituted by one or two substituents
selected from the group of (C.sub.1 -C.sub.3) lower alkyl, halogen, amino,
(C.sub.1 -C.sub.3) lower alkoxy, or (C.sub.1 -C.sub.3) lower alkyl amino;
the moiety:
##STR136##
is optionally substituted by (C.sub.1 -C.sub.3) lower alkyl, halogen, or
(C.sub.1 -C.sub.3) lower alkoxy;
R.sup.3 is --COAr, wherein Ar is a moiety selected from the group
consisting of:
##STR137##
wherein X is selected from O, S, --NH, --NCH.sub.3 and --NCOCH.sub.3 ;
R.sup.5 is selected from H, (C.sub.1 -C.sub.3) lower alkyl, halogen, or
(C.sub.1 -C.sub.3) lower alkoxy;
R.sup.6 is selected from:
(a) the moieties of the formulae:
##STR138##
wherein R.sup.1 and R.sup.2 are selected from H, lower alkyl (C.sub.1
-C.sub.3), lower alkoxy (C.sub.1 -C.sub.3) and halogen;
n is 1 or 2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or
cyclopentenyl;
R.sub.a is independently selected from hydrogen, --CH.sub.3, --C.sub.2 H5,
moieties of the formulae:
##STR139##
--(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 -C.sub.3) or --CH.sub.2
CH.sub.2 OH;
q is one or two;
R.sub.b is independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5
;
(b) a moiety of the formula:
##STR140##
wherein J is R.sub.a, lower alkyl (C.sub.3 -C.sub.8) branched or
unbranched, lower alkenyl (C.sub.3 -C.sub.8) branched or unbranched,
--O-lower alkyl (C.sub.3 -C.sub.8) branched or unbranched, --O-lower
alkenyl (C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran,
tetrahydrothiophene, the moieties:
##STR141##
or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3) lower alkoxy, halogen,
tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR142##
wherein D, E, F and G are selected from carbon or nitrogen and wherein the
carbon atoms may be optionally substituted with halogen, (C.sub.1
-C.sub.3) lower alkyl, hydroxy, --CO-lower alkyl (C.sub.1 -C.sub.3), CHO,
(C.sub.1 -C.sub.3)lower alkoxy, or --CO.sub.2 -lower alkyl (C.sub.1
-C.sub.3), and R.sub.a and R.sub.b are as hereinbefore defined;
(c) a moiety of the formula:
##STR143##
wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3) lower alkyl,
--O-lower alkyl (C.sub.1 -C.sub.3), OH,
##STR144##
wherein Ar' is selected from the moieties of the formula:
##STR145##
R.sub.a and R.sub.b are as hereinbefore defined; R.sup.4 is selected from
H, lower alkyl (C.sub.1 -C.sub.3), --CO-lower alkyl (C.sub.1 -C.sub.3);
(d) a moiety selected from:
--M-lower alkyl (C.sub.3 -C.sub.8), --M--(CH.sub.2).sub.p
-cycloalkyl(C.sub.3 -C.sub.6), --M-lower alkenyl(C.sub.3 -C.sub.8),
##STR146##
wherein p is 0 to 4;
M is selected from O, S, NH or NHCH.sub.3 ;
R.sup.1, R.sup.2 and R.sub.a are as hereinbefore defined;
wherein
W' is selected from O, S, NH, N-lower alkyl (C.sub.1 -C.sub.3), --NCO-lower
alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
R.sup.7 is selected from H, lower alkyl (C.sub.1 -C.sub.3), halogen,
O-lower alkyl (C.sub.1 -C.sub.3), and CF.sub.3 ;
R.sup.8 and R.sup.9 are independently selected from H, lower alkyl (C.sub.1
-C.sub.3), --S-lower alkyl (C.sub.1 -C.sub.3), halogen, --NH-lower alkyl
(C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --OH,
--CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, --O-lower alkyl (C.sub.1
-C.sub.3), NHCO lower alkyl (C.sub.1 -C.sub.3), --O--CO-lower alkyl
(C.sub.1 -C.sub.3), and --CF.sub.3 ; and
or a pharmaceutically acceptable salt, ester or prodrug form thereof.
2. A compound of claim 1 which is
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phe
nyl!-2-fluoro-5-chlorobenzamide or a pharmaceutically acceptable salt,
ester or prodrug form thereof.
3. A compound of claim 1 which is
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phe
nyl!-2-chloro-pyridine-3-carboxamide or a pharmaceutically acceptable salt,
ester or prodrug form thereof.
4. A compound of claim 1 which is
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-
pyridinyl!›1,1'-biphenyl!-2-carboxamide or a pharmaceutically acceptable
salt, ester or prodrug form thereof.
5. A compound according to claim 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phe
nyl!-5-fluoro-2-methylbenzamide.
6. A compound according to claim 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-
chlorophenyl!-5-fluoro-2-methylbenzamide.
7. A compound according to claim 1
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-
pyridinyl!-5-fluoro-2-methylbenzamide.
8. A compound according to claim 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!phe
nyl!-5-fluoro-2-methylbenzamide.
9. A compound according to claim 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-
chlorophenyl!-5-fluoro-2-methylbenzamide.
10. A compound according to claim 1
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-
pyridinyl!-5-fluoro-2-methylbenzamide.
11. A compound according to claim 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!phe
nyl!›1,1'-biphenyl!-2-carboxamide.
12. A pharmaceutical composition useful for treating disease in a mammal
characterized by excess renal reabsorption of water, the pharmaceutical
composition comprising an effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt, ester or prodrug form thereof, and a
suitable pharmaceutical carrier.
13. The pharmaceutical composition of claim 12 wherein the disease in a
mammal characterized by excess renal reabsorption of water is congestive
heart failure, nephrotic syndrome, hyponatremia, coronary vasospasm,
cardiac ischemia0 renal vasospasm, liver cirrhosis, brain edema, cerebral
ischemia, or cerebral hemorrhage-stroke.
14. A method for treating disease in a mammal characterized by excess renal
reabsorption of water, the method comprising administering to a mammal in
need thereof an effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt, ester or prodrug form thereof, and a
suitable pharmaceutical carrier.
15. The method of claim 14 wherein the disease in a mammal characterized by
excess renal reabsorption of water is congestive heart failure, nephrotic
syndrome, hyponatremia, coronary vasospasm, cardiac ischemia, renal
vasospasm, liver cirrhosis, brain edema, cerebral ischemia, or cerebral
hemorrhage stroke.
16. A compound selected from Formula I:
##STR147##
wherein: the moiety:
##STR148##
is optionally substituted by (C.sub.1 -C.sub.3) lower alkyl, halogen, or
(C.sub.1 -C.sub.3) lower alkoxy;
R.sup.3 is --COAr, wherein Ar is a moiety selected from the group
consisting of:
##STR149##
wherein X is selected from O, S, --NH, --NCH.sub.3 and --NCOCH.sub.3 ;
R.sup.5 is selected from H, (C.sub.1 -C.sub.3) lower alkyl, halogen, or
(C.sub.1 -C.sub.3) lower alkoxy;
R.sup.6 is selected from:
(a) the moieties of the formulae:
##STR150##
wherein R.sup.1 and R.sup.2 are selected from H, lower alkyl (C.sub.1
-C.sub.3), lower alkoxy (C.sub.1 -C.sub.3) and halogen;
n is 1 or 2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or
cyclopentenyl;
R.sub.a is independently selected from hydrogen, --CH.sub.3, --C.sub.2
H.sub.5, moieties of the formulae:
##STR151##
--(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 -C.sub.3) or --CH.sub.2
CH.sub.2 OH;
q is one or two;
R.sub.b is independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5
;
(b) a moiety of the formula:
##STR152##
wherein J is R.sub.a, lower alkyl (C.sub.3 -C.sub.8) branched or
unbranched, lower alkenyl (C.sub.3 -C.sub.8) branched or unbranched,
--O-lower alkyl (C.sub.3 -C.sub.8) branched or unbranched, --O-lower
alkenyl (C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran,
tetrahydrothiophene, the moieties:
##STR153##
or --CH.sub.2 -K' wherein K' is (C.sub.1 -C.sub.3) lower alkoxy, halogen,
tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR154##
wherein D, E, F and G are selected from carbon or nitrogen and wherein the
carbon atoms may be optionally substituted with halogen, (C.sub.1
-C.sub.3) lower alkyl, hydroxy, --CO-lower alkyl (C.sub.1 -C.sub.3), CHO,
(C.sub.1 -C.sub.3)lower alkoxy, or --CO.sub.2 -lower alkyl (C.sub.1
-C.sub.3), and R.sub.a and R.sub.b are as hereinbefore defined;
(c) a moiety of the formula:
##STR155##
wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3) lower alkyl,
--O-lower alkyl(C.sub.1 -C.sub.3), OH,
##STR156##
wherein Ar' is selected from the moieties of the formula:
##STR157##
R.sub.a and R.sub.b are as hereinbefore defined; R.sup.4 is selected from
H, lower alkyl (C.sub.1 -C.sub.3), --CO-lower alkyl (C.sub.1 -C.sub.3);
(d) a moiety selected from:
--M-lower alkyl (C.sub.3 -C.sub.8), --M--(CH.sub.2).sub.p
-cycloalkyl(C.sub.3 -C.sub.6), --M-lower alkenyl(C.sub.3 -C.sub.8),
##STR158##
wherein p is 0 to 4;
M is selected from O, S, NH or NHCH.sub.3 ;
R.sup.1, R.sup.2 and R.sub.a are as hereinbefore defined;
wherein
W' is selected from O, S, NH, N-lower alkyl (C.sub.1 -C.sub.3), --NCO-lower
alkyl (C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
R.sup.7 is selected from H, lower alkyl (C.sub.1 -C.sub.3), halogen,
O-lower alkyl (C.sub.3 -C.sub.3), and CF.sub.3 ;
R.sup.8 and R.sup.9 are independently selected from H, lower alkyl (C.sub.1
-C.sub.3), --S-lower alkyl (C.sub.1 -C.sub.3), halogen, --NH-lower alkyl
(C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --OH,
--CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, --O-lower alkyl (C.sub.1
-C.sub.3), NHCO lower alkyl (C.sub.1 -C.sub.3), --O--CO-lower alkyl
(C.sub.1 -C.sub.3), and --CF.sub.3 ; and
or a pharmaceutically acceptable salt, ester or prodrug form thereof.
Description
FIELD OF THE INVENTION
This invention relates to new tricyclic non-peptide vasopressin antagonists
which are useful in treating conditions where decreased vasopressin levels
are desired, such as in congestive heart failure, in disease conditions
with excess renal water reabsorption and in conditions with increased
vascular resistance and coronary vasoconstriction.
BACKGROUND OF THE INVENTION
Vasopressin is released from the posterior pituitary either in response to
increased plasma osmolarity detected by brain osmoreceptors or decreased
blood volume and blood pressure sensed by low-pressure volume receptors
and arterial baroreceptors. The hormone exerts its action through two well
defined receptor subtypes: vascular V.sub.1 and renal epithelial V.sub.2
receptors. Vasopressin-induced antidiuresis, mediated by renal epithelial
V.sub.2 receptors, helps to maintain normal plasma osmolarity, blood
volume and blood pressure.
Vasopressin is involved in some cases of congestive heart failure where
peripheral resistance is increased. V.sub.1 antagonists may decrease
systemic vascular resistance, increase cardiac output and prevent
vasopressin induced coronary vasoconstriction. Thus, in conditions with
vasopressin induce increases in total peripheral resistance and altered
local blood flow, V.sub.1 -antagonists may be therapeutic agents. V.sub.1
antagonists may decrease blood pressure, induced hypotensive effects and
thus be therapeutically useful in treatment of some types of hypertension.
The blockage of V.sub.2 receptors is useful in treating diseases
characterized by excess renal reabsorption of free water. Antidiuresis is
regulated by the hypothalamic release of vasopressin (antidiuretic
hormone) which binds to specific receptors on renal collecting tubule
cells. This binding stimulates adenylyl cyclase and promotes the
cAMP-mediated incorporation of water pores into the luminal surface of
these cells. V.sub.2 antagonists may correct the fluid retention in
congestive heart failure, liver cirrhosis, nephritic syndrome, central
nervous system injuries, lung disease and hyponatremia.
Elevated vasopressin levels occur in congestive heart failure which is more
common in older patients with chronic heart failure. In patients with
hyponatremic congestive heart failure and elevated vasopressin levels, a
V.sub.2 antagonist may be beneficial in promoting free water excretion by
antagonizing the action of antidiuretic hormone. On the basis of
biochemical and pharmacological effects of the hormone, antagonists of
vasopressin are expected to be therapeutically useful in the treatment
and/or prevention of hypertension, cardiac insufficiency, coronary
vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive
heart failure, nephritic syndrome, brain edema, cerebral ischemia,
cerebral hemorrhage-stroke, thrombosis-bleeding and abnormal states of
water retention.
The following prior art references describe peptide vasopressin
antagonists: M. Manning et al., J. Med. Chem., 35, 382(1992); M. Manning
et al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Pat.
No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No.
5,055,448(1991) F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffolo et
al., Drug News and Perspective, 4(4), 217, (May) (1991). P. D. Williams et
al., have reported on potent hexapeptide oxytocin antagonists ›J. Med.
Chem., 35, 3905(1992)! which also exhibit weak vasopressin antagonist
activity in binding to V.sub.1 and V.sub.2 receptors. Peptide vasopressin
antagonists suffer from a lack of oral activity and many of these peptides
are not selective antagonists since they also exhibit partial agonist
activity.
Non-peptide vasopressin antagonists have recently been disclosed, Y.
Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J.
Pharmacol, 105, 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP
0514667-A1; EPO 382185-A2; WO9105549 and U.S. Pat. No. 5,258,510; WO
9404525 Yamanouchi Pharm. Co., Ltd., WO 9420473; WO 9412476; WO 9414796;
Fujisawa Co. Ltd., EP 620216-A1 Ogawa et al, (Otsuka Pharm. Co.) EP
470514A disclose carbostyril derivatives and pharmaceutical compositions
containing the same. Non-peptide oxytocin and vasopressin antagonist have
been disclosed by Merck and Co.; M. G. Bock and P. D. Williams, EP
0533242A; M. G. Bock et al., EP 0533244A; J. M. Erb, D. F. Verber, P. D.
Williams, EP 0533240A; K. Gilbert et al., EP 0533243A.
Premature birth can cause infant health problems and mortality and a key
mediator in the mechanism of labor is the peptide hormone oxytocin. On the
basis of the pharmacological action of oxytocin, antagonists of this
hormone are useful in the prevention of preterm labor, B. E. Evans et al.,
J. Med. Chem. 35, 3919(1992), J. Med. Chem., 36, 3993(1993) and references
therein. The compounds of this invention are antagonists of the peptide
hormone oxytocin and are useful in the control of premature birth.
The present invention relates to novel tricyclic derivatives which exhibit
antagonist activity at V.sub.1 and/or V.sub.2 receptors and exhibit in
vivo pressin antagonist activity. The compounds also exhibit antagonists
activity of oxytocin receptors.
SUMMARY OF THE INVENTION
This invention relates to new compounds selected from those of the general
Formula I:
##STR2##
wherein Y is a bond or a moiety selected from --(CH.sub.2)--, --CHOH,
--CHO-lower alkyl(C.sub.1 -C.sub.6), --CH--S-lower alkyl(C.sub.1
-C.sub.6), --CHNH.sub.2, --CHN-lower alkyl(C.sub.1 -C.sub.6), --C›N-lower
alkyl(C.sub.1 -C.sub.6)!.sub.2,
##STR3##
--CHOCO-lower alkyl(C.sub.1 -C.sub.6), --CHNH(CH.sub.2).sub.m NH.sub.2 ;
--CHNH(CH.sub.2).sub.m --NH-lower alkyl(C.sub.1 -C.sub.6),
--CHNH(CH.sub.2).sub.m --N›lower alkyl(C.sub.1 -C.sub.6)!.sub.2 ;
--CHNH(CH.sub.2).sub.m --S-lower alkyl(C.sub.1 -C.sub.6),
--CHNH(CH.sub.2).sub.m --O-lower alkyl(C.sub.1 -C.sub.6),
##STR4##
S, O, --NH, --N-lower alkyl(C.sub.1 -C.sub.6), --NCO-lower alkyl(C.sub.1
-C.sub.6), m is an integer of 2 to 6; A--B is a moiety selected from
##STR5##
wherein n is an integer 1 or 2 provided that when Y is a bond, n is 2; and
the moiety:
##STR6##
represents: (1) an unsaturated 6-membered heterocyclic aromatic ring
containing one nitrogen atom, optionally substituted by one or two
substitutents selected from (C.sub.1 -C.sub.3)lower alkyl, halogen, amino,
(C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3)lower alkylamino; and
wherein the pyridine ring nitrogen is optionally substituted on the
nitrogen atom with oxygen to form an N-oxide; (2) a 5-membered aromatic
(unsaturated) heterocyclic ring having one heteroatom selected from O, or
S; and the moiety:
##STR7##
represents: (1) an unsaturated 6-membered heterocyclic aromatic ring
containing one or two nitrogen atoms, optionally substituted by one or two
substituents selected from (C.sub.1 -C.sub.3)lower alkyl, halogen, amino,
(C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3)lower alkylamino; (2)
a 5-membered aromatic (unsaturated) heterocyclic ring having one
heteroatom selected from O, N or S; (3) a 5-membered aromatic
(unsaturated) heterocyclic ring having two adjacent nitrogen atoms; (4) a
5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen
atom together with either one oxygen or one sulfur atom; wherein the 5 or
6-membered heterocyclic rings are optionally substituted by (C.sub.1
-C.sub.3)lower alkyl, halogen, or (C.sub.1 -C.sub.3)lower alkoxy;
R.sup.3 is --COAr, wherein Ar is a moiety selected from the group
consisting of:
##STR8##
wherein X is selected from O, S, --NH, --NCH.sub.3 and --NCOCH.sub.3 ;
R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3),
--CO-lower alkyl(C.sub.1 -C.sub.3),
R.sup.1 and R.sup.2 are selected from hydrogen, (C.sub.1 -C.sub.3)lower
alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen; R.sup.5 is selected
from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower
alkoxy and halogen; R.sup.6 is selected from (a) moieties of the formulae:
##STR9##
wherein cycloalkyl is defined as (C.sub.3 -C.sub.6) cycloalkyl,
cyclohexenyl or cyclopentenyl; and R.sub.a is independently selected from
hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5,
##STR10##
--(CH.sub.2).sub.q --O-lower alkyl(C.sub.1 -C.sub.3), --CH.sub.2 H.sub.2
OH, q is one, two, or three, R.sub.b is independently selected from
hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5,
(b) a moiety of the formula:
##STR11##
wherein J is R.sub.a, lower alkyl(C.sub.3 -C.sub.8) branched or
unbranched, lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched,
O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, --O-lower
alkenyl(C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran,
tetrahydrothiophene, and the moieties:
##STR12##
or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3)-lower alkoxy, halogen,
tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety:
##STR13##
wherein D, E, F and G are selected from carbon or nitrogen and wherein the
carbon atoms may be optionally substituted with halogen, (C.sub.1
-C.sub.3) lower alkyl, hydroxy, --CO-lower alkyl(C.sub.1 -C.sub.3), CHO,
(C.sub.1 -C.sub.3)lower alkoxy, --CO.sub.2 -lower alkyl(C.sub.1 -C.sub.3),
and R.sub.a and R.sub.b are as hereinbefore defined;
(c) a moiety of the formula:
##STR14##
wherein R.sub.a and R.sub.b are as hereinbefore defined; (d) a moiety of
the formula:
--M--R.sub.d
wherein R.sub.d is lower alkyl(C.sub.3 -C.sub.8), lower alkenyl(C.sub.3
-C.sub.8), --(CH.sub.2).sub.p -cycloalkyl(C.sub.3 -C.sub.6), when M is O,
S, NH, NCH.sub.3 and the moiety --M--R.sub.d wherein R.sub.d is selected
from the moieties:
##STR15##
wherein p is zero to four and M is a bond or M is selected from O, S, NH,
NCH.sub.3 ; wherein R.sup.1, R.sup.2 and R.sub.a are as hereinbefore
defined;
wherein Ar' is selected from moieties of the formula:
##STR16##
wherein W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3)
NHCO-lower alkyl(C.sub.1 -C.sub.3), and NSO.sub.2 lower alkyl(C.sub.1
-C.sub.3);
R.sup.7 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3), halogen,
O-lower alkyl(C.sub.1 -C.sub.3) and CF.sub.3 ; R.sup.8 and R.sup.9 are
independently selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3),
--S-lower alkyl(C.sub.1 -C.sub.3), halogen, --NH-lower alkyl(C.sub.1
-C.sub.3), --N-›lower alkyl(C.sub.1 -C.sub.3)!.sub.2, --OCF.sub.3, --OH,
--CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, O-lower alkyl(C.sub.1
-C.sub.3), NHCO lower alkyl(C.sub.1 -C.sub.3), --O--CO-lower alkyl
(C.sub.1 -C.sub.3) and CF.sub.3 and;
R.sup.10 is selected from hydrogen, halogen, lower alkyl(C.sub.1 -C.sub.3),
--NH-lower alkyl (C.sub.1 -C.sub.3), --N-›lower alkyl(C.sub.1
-C.sub.3)!.sub.2, --O-lower alkyl(C.sub.1 -C.sub.3),
--N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ; and the pharmaceutically
acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Within the group of the compounds defined by Formula I, certain subgroups
of compounds are broadly preferred. Broadly preferred are those compounds
wherein R.sup.3 is the moiety:
##STR17##
and Ar is selected from the moiety:
##STR18##
wherein R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.5, R.sup.6 and R.sup.7
are as herein-before defined.
Especially preferred are compounds wherein R.sup.3 is the moiety:
##STR19##
Ar is selected from the moiety:
##STR20##
wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl,
cyclohexenyl or cyclopentenyl;
R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.7 as
hereinbefore defined;
and Ar' is selected from the moieties:
##STR21##
wherein R.sup.8, R.sup.9, R.sup.10 and W' are as hereinbefore defined.
Also especially preferred are compounds wherein Y is CH.sub.2, --CHOH,
--CHNH.sub.2, --CHNH-lower alkyl(C.sub.1 -C.sub.3), --CHN›lower
alkyl(C.sub.1 -C.sub.3)!.sub.2 and --CHO-lower alkyl(C.sub.1 -C.sub.3);
and R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 are as hereinbefore defined.
The most preferred of the compounds of Formula I are those wherein Y is
CH.sub.2, --CHOH, --CHNH.sub.2, --CHNH-lower alkyl (C.sub.1 -C.sub.3),
--CHN›lower alkyl (C.sub.1 -C.sub.3)!.sub.2 and --CHO-lower alkyl (C.sub.1
-C.sub.3);
R.sub.3 is the moiety
##STR22##
Ar is selected from the moieties:
##STR23##
(CH.sub.2).sub.n -cycloalkyl wherein cycloalkyl is defined as (C.sub.3
-C.sub.6) cycloalkyl, cyclohexenyl or cyclopentenyl; R.sub.a, R.sub.b,
R.sup.1, R.sup.2, R.sup.5, R.sup.7 are as hereinbefore defined;
and Ar' is a moiety:
##STR24##
wherein R.sup.8, R.sup.9, and R.sup.10 are as previously defined.
The most highly broadly preferred of the compounds of Formula I are those
wherein Y is a bond or CH.sub.2, --CHOH, --CHNH.sub.2, --CHNH-lower
alkyl(C.sub.1 -C.sub.3), --CHN›lower alkyl(C.sub.1 -C.sub.3)!.sub.2 and
--CHO lower alkyl(C.sub.1 -C.sub.3), wherein the moiety:
##STR25##
is an unsubstituted or substituted thiophene, furan, pyrrole, or pyridine
ring; and wherein the moiety:
##STR26##
is (1) an unsaturated 6-membered heterocyclic aromatic ring containing one
or two nitrogen atoms; (2) a 5-membered aromatic (unsaturated)
heterocyclic ring having one heteroatom selected from O, N, or S; (3) a
5-membered aromatic (unsaturated) heterocyclic ring having two adjacent
nitrogen atoms.
R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9, and R.sup.10 are as previously defined;
R.sup.3 is the moiety:
##STR27##
wherein Ar is:
##STR28##
and R.sup.6 is selected from the group
##STR29##
where Ar' is selected from the group
##STR30##
and W' and cycloalkyl are as previously described.
More particularly preferred are compounds of the formula:
##STR31##
wherein D is --CH or N; R.sup.3 is the moiety:
##STR32##
wherein Ar is selected from the moieties:
##STR33##
and Ar' is selected from the moieties:
##STR34##
wherein R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.5, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, cycloalkyl and W' are as hereinbefore described.
Also particularly preferred are compounds of the formula:
##STR35##
wherein D is --CH or N; R.sup.3 is the moiety:
##STR36##
wherein Ar is selected from the moieties:
##STR37##
Ar' is selected from the moieties:
##STR38##
wherein R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.8,
R.sup.9, R.sup.10, cycloalkyl M, R.sub.d, and W' are as hereinbefore
described.
More particularly preferred are compounds of the formulae:
##STR39##
wherein Y is selected from --CH.sub.2, --CHOH, --CHNH.sub.2, --CHNH-lower
alkyl(C.sub.1 -C.sub.3), --CHN›lower alkyl(C.sub.1 -C.sub.3)!.sub.2 and
--CHO lower alkyl(C.sub.1 -C.sub.3); and the moiety:
##STR40##
represents: (1) an unsaturated 6-membered heterocyclic aromatic ring
containing one nitrogen atom, optionally substituted by one or two
substituents selected from (C.sub.1 -C.sub.3)lower alkyl, halogen, amino,
(C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3)lower alkylamino; (2)
a 5-membered aromatic (unsaturated) heterocyclic ring having one
heteroatom selected from O, N or S; (3) a 5-membered aromatic
(unsaturated) heterocyclic ring having two adjacent nitrogen atoms;
wherein the 5 or 6-membered heterocyclic rings are optionally substituted
by (C.sub.1 -C.sub.3)lower alkyl, halogen, or (C.sub.1 -C.sub.3)lower
alkoxy;
R.sup.3 is the moiety:
##STR41##
wherein Ar is the moiety:
##STR42##
wherein R.sub.a is independently selected from hydrogen or --CH.sub.3 ;
Ar' is selected from the moieties:
##STR43##
wherein R.sup.1, R.sup.2, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
and W' are as hereinbefore described.
Also particularly preferred are compounds of the formulae:
##STR44##
wherein Y is selected from --CH.sub.2, --CHOH, --CHNH.sub.2, --CHNH-lower
alkyl(C.sub.1 -C.sub.3), --CHN›lower alkyl(C.sub.1 -C.sub.3)!.sub.2 and
--CHO lower alkyl (C.sub.1 -C.sub.3); and the moiety:
##STR45##
represents: (1) an unsaturated 6-membered heterocyclic aromatic ring
containing one nitrogen atom, optionally substituted by one or two
substituents selected from (C.sub.1 -C.sub.3)lower alkyl, halogen, amino,
(C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3)lower alkylamino; (2)
a 5-membered aromatic (unsaturated) heterocyclic ring having one
heteroatom selected from N or S;
R.sup.3 is the moiety:
##STR46##
wherein Ar is selected from the moieties:
##STR47##
R.sub.a is independently selected from hydrogen, --CH.sub.3 or --C.sub.2
H.sub.5 and Ar' is selected from the moieties:
##STR48##
wherein R.sup.1, R.sup.2, R.sup.5, R.sup.7, R.sup.8, R.sup.9, and R.sup.10
are as hereinbefore defined.
Among the more preferred compounds of this invention are those selected
from Formula I:
##STR49##
wherein Y is a bond, A--B is a moiety selected from
##STR50##
and the moiety:
##STR51##
represents: (1) an unsaturated 6-membered heterocyclic aromatic ring
containing one nitrogen atom, optionally substituted by one or two
substitutents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen,
amino, (C.sub.1 -C.sub.3) lower alkoxy or (C.sub.1 -C.sub.3)lower
alkylamino; and wherein the pyridine ring nitrogen is optionally
substituted on the nitrogen atom with oxygen to form an N-oxide; and the
moiety:
##STR52##
represents: (1) an unsaturated 5-membered heterocyclic aromatic ring
containing two adjacent nitrogen atoms, optionally substituted by one or
two substituents selected from (C.sub.1 -C.sub.3)lower alkyl, halogen,
amino, (C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3)lower
alkylamino;
R.sup.3 is --COAr, wherein Ar is a moiety selected from the group
consisting of:
##STR53##
wherein X is selected from O, S, --NH, --NCH.sub.3 and --NCOCH.sub.3 ;
R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3),
--CO-lower alkyl(C.sub.1 -C.sub.3),
R.sup.1 and R.sup.2 are selected from hydrogen, (C.sub.1 -C.sub.3)lower
alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen; R.sup.5 is selected
from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower
alkoxy and halogen; R.sup.6 is selected from (a) moieties of the formulae:
##STR54##
wherein n is 1 or 2;cycloalkyl is defined as (C.sub.3 -C.sub.6)
cycloalkyl, cyclohexenyl or cyclopentenyl; and R.sub.a is independently
selected from hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5,
##STR55##
--(CH.sub.2).sub.q --O-lower alkyl(C.sub.1 -C.sub.3), --CH.sub.2 H.sub.2
OH, q is one or two; R.sub.b is independently selected from hydrogen,
--CH.sub.3 or --C.sub.2 H.sub.5,
(b) a moiety of the formula
##STR56##
wherein J is R.sub.a, lower alkyl(C.sub.3 -C.sub.8) branched or
unbranched, lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched,
O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, --O-lower
alkenyl(C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran,
tetrahydrothiophene, and the moieties:
##STR57##
or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3)-lower alkoxy, halogen,
tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety:
##STR58##
wherein D, E, F and G are selected from carbon or nitrogen and wherein the
carbon atoms may be optionally substituted with halogen, (C.sub.1
-C.sub.3)lower alkyl, hydroxy, --CO-lower alkyl(C.sub.1 -C.sub.3), CHO,
(C.sub.1 -C.sub.3)lower alkoxy, --CO.sub.2 -lower alkyl(C.sub.1 -C.sub.3),
and R.sub.a and R.sub.b are as hereinbefore defined;
(c) a moiety of the formula:
##STR59##
wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3) lower alkyl,
--O-lower alkyl(C.sub.1 -C.sub.3), OH,
##STR60##
wherein R.sub.a and R.sub.b are as hereinbefore defined; (d) a moiety of
the formula: wherein R.sub.d is lower alkyl(C.sub.3 -C.sub.8), lower
alkenyl(C.sub.3 -C.sub.8), --(CH.sub.2).sub.p -cycloalkyl (C.sub.3
-C.sub.6), when M is O, S, NH, NCH.sub.3 and the moiety --M-R.sub.d
wherein R.sub.d is selected from the moieties:
##STR61##
wherein p is zero to four and M is a bond or M is selected from O, S, NH,
NCH.sub.3 ; wherein R.sup.1, R.sup.2 and R.sub.a are as hereinbefore
defined;
wherein Ar' is selected from moieties of the formula:
##STR62##
wherein W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3)
NHCO-lower alkyl(C.sub.1 -C.sub.3), and NSO.sub.2 lower alkyl(C.sub.1
-C.sub.3); R.sup.7 is selected from hydrogen, lower alkyl(C.sub.1
-C.sub.3), halogen, O-lower alkyl(C.sub.1 -C.sub.3) and CF.sub.3 ; R.sup.8
and R.sup.9 are independently selected from hydrogen, lower alkyl(C.sub.1
-C.sub.3), --S-lower alkyl(C.sub.1 -C.sub.3), halogen, --NH-lower
alkyl(C.sub.1 -C.sub.3), --N-›lower alkyl(C.sub.1 -C.sub.3)!.sub.2,
--OCF.sub.3, --OH, --CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, O-lower
alkyl(C.sub.1 -C.sub.3), NHCO lower alkyl(C.sub.1 -C.sub.3), --O--CO-lower
alkyl(C.sub.1 -C.sub.3) and CF.sub.3 and; R.sup.10 is selected from
hydrogen, halogen, lower alkyl(C.sub.1 -C.sub.3), --NH-lower alkyl(C.sub.1
-C.sub.3), --N-›lower alkyl(C.sub.1 -C.sub.3)!.sub.2, --O-lower
alkyl(C.sub.1 -C.sub.3), --N(R.sub.b) (CH.sub.2).sub.q --N(R.sub.b).sub.2,
and the pharmaceutically acceptable salts thereof.
Within the group above are the following preferred sub-groups 1 to 3 of
compounds:
1. wherein A--B is a moiety:
##STR63##
wherein R.sup.3 is as defined in claim 1; 2. wherein A--B is a moiety:
##STR64##
wherein R.sup.3 is as defined in claim 1; 3. compounds of the formula:
##STR65##
wherein Y is a bond; A--B is
##STR66##
wherein the moiety:
##STR67##
represents: A 5-membered aromatic (unsaturated) heterocyclic ring having
two adjacent nitrogen atoms; wherein the 5-membered heterocyclic ring is
optionally substituted by (C.sub.1 -C.sub.3)lower alkyl, halogen, amino or
(C.sub.1 -C.sub.3)lower alkoxy or (C.sub.1 -C.sub.3) lower alkylamino; and
wherein the pyridine ring is optionally substituted on the nitrogen atom
with oxygen to form an N-oxide. R.sup.3 is --COAr, wherein Ar is a moiety
selected from the group consisting of:
##STR68##
wherein X is selected from O, S, --NH, --NCH.sub.3 and --NCOCH.sub.3 ;
R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3),
--CO-lower alkyl(C.sub.1 -C.sub.3),
R.sup.1 and R.sup.2 are selected from hydrogen, (C.sub.1 -C.sub.3)lower
alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen; R.sup.5 is selected
from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower
alkoxy and halogen; R.sup.6 is selected from (a) moieties of the formulae:
##STR69##
wherein cycloalkyl is defined as (C.sub.3 -C.sub.6) cycloalkyl,
cyclohexenyl or cyclopentenyl; and R.sub.a is independently selected from
hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5,
##STR70##
--(CH.sub.2).sub.q --O-lower alkyl(C.sub.1 -C.sub.3), --CH.sub.2 H.sub.2
OH, q is one, two, or three, R.sub.b is independently selected from
hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5,
(b) a moiety of the formula:
##STR71##
wherein J is R.sub.a, lower alkyl(C.sub.3 -C.sub.8) branched or
unbranched, lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched,
O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, --O-lower alkenyl
(C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran,
tetrahydrothiophene, and the moieties:
##STR72##
or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3)-lower alkoxy, halogen,
tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety:
##STR73##
wherein D, E, F and G are selected from carbon or nitrogen and wherein the
carbon atoms may be optionally substituted with halogen, (C.sub.1
-C.sub.3)lower alkyl, hydroxy, --CO-lower alkyl(C.sub.1 -C.sub.3), CHO,
(C.sub.1 -C.sub.3)lower alkoxy, --CO.sub.2 -lower alkyl(C.sub.1 -C.sub.3),
and R.sub.a and R.sub.b are as hereinbefore defined;
(c) a moiety of the formula:
##STR74##
wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3) lower alkyl,
--O-lower alkyl(C.sub.1 -C.sub.3), OH,
##STR75##
wherein R.sub.a and R.sub.b are as hereinbefore defined; (d) a moiety of
the formula:
--M-R.sub.d
wherein R.sub.d is lower alkyl(C.sub.3 -C.sub.8), lower alkenyl(C.sub.3
-C.sub.8), --(CH.sub.2).sub.p -cycloalkyl(C.sub.3 -C.sub.6) when M is O,
S, NH, NCH.sub.3, and the moiety --M-R.sub.d wherein R.sub.d is selected
from the moieties:
##STR76##
wherein p is zero to four and M is a bond or M is selected from O, S, NH,
NCH.sub.3 ; wherein R.sup.1, R.sup.2 and R.sub.a are as hereinbefore
defined;
wherein Ar' is selected from moieties of the formula:
##STR77##
wherein W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3)
NHCO-lower alkyl(C.sub.1 -C.sub.3), and NSO.sub.2 lower alkyl(C.sub.1
-C.sub.3); R.sup.7 is selected from hydrogen, lower alkyl(C.sub.1
-C.sub.3), halogen, O-lower alkyl(C.sub.1 -C.sub.3) and CF.sub.3 ;R.sup.8
and R.sup.9 are independently selected from hydrogen, lower alkyl(C.sub.1
-C.sub.3), --S-lower alkyl(C.sub.1 -C.sub.3), halogen, --NH-lower
alkyl(C.sub.1 -C.sub.3), --N-›lower alkyl(C.sub.1 -C.sub.3)!.sub.2,
--OCF.sub.3, --OH, --CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, O-lower
alkyl(C.sub.1 -C.sub.3), NHCO lower alkyl(C.sub.1 -C.sub.3), --O--CO-lower
alkyl(C.sub.1 -C.sub.3) and CF.sub.3 and; R.sup.10 is selected from
hydrogen, halogen, lower alkyl(C.sub.1 -C.sub.3), --NH-lower alkyl(C.sub.1
-C.sub.3), --N-›lower alkyl(C.sub.1 -C.sub.3)!.sub.2, --O-lower
alkyl(C.sub.1 -C.sub.3), --N(R.sub.b) (CH.sub.2).sub.q --N(R.sub.b).sub.2
; and the pharmaceutically acceptable salts thereof.
Among the more preferred compounds of this invention are those selected
from:
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2-methylbenzamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-5-fluoro-2-methylbenzamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-2-methylpyridine-3-carboxamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-fluoro-2-methylbenzamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-chloro-2-fluoro-benzamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl)-3-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!›1,1'-biphenyl!-2-carboxamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-2-(dimethylamino)pyridine-3-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2-methyl-benzamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-5-fluoro-2-methylbenzamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-fluoro-2-methylbenzamide.
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-2-(dimethylamino)pyradine-3-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-2-chloropyridine-3-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!phen
yl!›1,1'-biphenyl!-2-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-m
ethylphenyl!›1,1'-biphenyl!-2-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-m
ethylphenyl!›1,1'-biphenyl!-2-carboxamide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!!phe
nyl!›1,1'-biphenyl!-2-carboxamide, 7-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide, 7-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!›phe
nyl!›1,1'-biphenyl!-2-carboxamide, 10-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide,10-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2-methylbenzamide,10-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-5-fluoro-2-methylbenzamide,10-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-m
ethylphenyl!-5-fluoro-2-methylbenzamide,10-N-oxide.
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-m
ethylphenyl!›1,1'-biphenyl!-2-carboxamide,10-N-oxide.
Compounds of this invention may be prepared as shown in Scheme I by
reaction of azepine derivatives of Formula 3 with a substituted or
unsubstituted 4-nitrobenzoyl chloride 4a or a substituted or unsubstituted
6-aminopyridine-3-carbonyl chloride 4b to give the intermediate 5a and 5b.
Reduction of the nitro group in intermediate 5 gives the 4-aminobenzoyl
derivative 6a and the 6-aminonicotinoyl derivative 6b. The reduction of
the nitro group in intermediate 5 may be carried out under catalytic
reduction conditions (hydrogen-Pd/C; Pd/C-hydrazine-ethanol) or under
chemical reduction conditions (SnCl.sub.2 -ethanol; Zn-acetic acid
TiCl.sub.3) and related reduction conditions known in the art for
converting a nitro group to an amino group. The conditions for conversion
of the nitro group to the amino group are chosen on the basis of
compatability with the preservation of other functional groups in the
molecule.
Reaction of compounds of Formula 6 with aroyl chloride or related activated
aryl carboxylic acids in solvents such as chloroform, dichloromethane,
dioxane, tetrahydrofuran, toluene and the like in the presence of a
tertiary base such as triethylamine and diisopropylethylamine or pyridine
and the like, affords the compounds 8 which are vasopressin antagonists.
##STR78##
Reaction of tricyclic derivatives of Formula 6 with either a carbamoyl
derivative 9 or a isocyanate derivative 10 gives compounds (Scheme 2) of
Formula 11 which are vasopressin antagonists of Formula I wherein R.sup.6
is
##STR79##
Reaction of tricyclic derivatives of Formula 6 with arylacetic acids,
activated as the acid chlorides 12, anhydrides, mixed anhydrides or
activated with known activating reagents, gives compounds 13 (Scheme 3).
##STR80##
The compounds of Formula I wherein Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are as defined and the moiety:
##STR81##
is as previously defined and the Ar' moiety is:
##STR82##
and R.sup.10 is --NH lower alkyl(C.sub.1 -C.sub.3) and --N-›lower
alkyl(C.sub.1 -C.sub.3)!.sub.2 may be prepared, as shown in Scheme 4, by
reacting the tricyclic derivatives 6a and 6b with a pyridinecarbonyl
chloride 14to give the derivatives 15. The derivatives 15 are reacted with
the appropriate mono alkylamines or dialkylamines to give vasopressin
antagonists of formulae 16.
##STR83##
The compounds of Formula I wherein E, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.5, and R.sup.7 are as defined and the R.sup.3 (--COAr) aryl group is
##STR84##
wherein R.sup.6 is --M--R.sub.d wherein M is O, S, NH, N--CH.sub.3 and
R.sub.d is as previously defined may be prepared as shown in Scheme 5 by
first converting the azepine derivatives 3 into the intermediate 17 and
then reacting these nicotinolyl intermediates with derivatives of the
formulae: HM-R.sub.d in the presence of a non-nucleophilic base such as
N,N-diisopropylethylamine to give products 18. The best results are
obtained in the displacement of the halogen in the pyridine intermediates
17, when the halogen atom is a fluoro group. With nucleophilic amines
(M=NH, NCH.sub.3) the reaction can be carried out with the 6-chloro, bromo
or fluoro derivatives 17 in (1) the absence of a non-nucloephilic base;
(2) in a non-nucleophilic solvent; or (3) with excess amine and no
solvent. With derivatives HOR.sub.d the 6-fluoro derivative 17 is required
for satisfactory conversion of 17 to 18.
##STR85##
Alternatively, the products 18 may be prepared by first forming derivatives
of the Formula 19 and then coupling these derivatives with the azepine
compounds 3 (Scheme 6). The carboxylic acid intermediates are activated
for coupling to the azepine compounds 3 by reaction with peptide coupling
reagents, or preferably by conversion to the acid chlorides, anhydrides or
mixed anhydrides.
##STR86##
As an alternative method for synthesis of compounds of this invention as
depicted in Formula I wherein R.sub.a, R.sub.b, R.sup.1, R.sup.2, R.sup.5,
R.sup.7, A, and Y are as previously defined and R.sup.3 is
##STR87##
is the coupling of aryl carboxylic acids 20 with the azepine derivative 3.
(Scheme 7)
The aryl carboxylic acids are activated for coupling by conversion to an
acid chloride, bromide or anhydride or by first reacting with an
activating reagent such as N,N-dicyclocarbodiimide, diethyl cyanophosphate
and related "peptide type" activating reagents. The method of activating
the acids 20 for coupling to the azepine derivative 3 is chosen on the
basis of compatibility with other substituent groups in the molecule. The
method of choice is the conversion of the aryl carboxylic acid 20 to the
corresponding aroyl chloride. The aryl acid chlorides 21 may be prepared
by standard procedures known in the art, such as reaction with thionyl
chloride, oxalyl chloride and the like. The coupling reaction is carried
out in solvents such as halogenated hydrocarbons, toluene, xylene,
tetrahydrofuran, dioxane in the presence of pyridine or tertiary bases
such as triethylamine and the like (Scheme 7). Alternatively, the aroyl
chlorides, prepared from the aryl carboxylic acids 20 may be reacted with
derivatives 3 in pyridine with or without 4-(dimethylamino)pyridine to
give derivatives 22.
In general, when the aryl carboxylic acids are activated with
N,N-carbonyldiimidazole and other "peptide type" activating reagents,
higher temperatures are required than when the aroyl chlorides are used.
The reaction may be carried out in a higher boiling solvent xylene or
without a solvent (100.degree. C. to 150.degree. C).
The activation of aryl carboxylic by conversation to the acid chlorides
with thionyl chloride or oxalyl chloride is preferred since the more
reactive aroyl chlorides give better yields of product. The synthesis of
selected examples is illustrated in Scheme 7.
##STR88##
The synthesis of compounds of Formula I wherein R.sup.3 is
##STR89##
the Ar group is
##STR90##
and where Ar' is as previously defined is carried out according to Scheme
8. The azepine compounds are reacted with mono-methyl terephythalyl
chloride 23 (prepared from mono-methyl terephthalate and thionyl chloride)
in the presence of a tertiary base such as triethylamine in solvents such
as dichloromethane, tetrahydrofuran, dioxane, toluene add the like to give
derivatives 24 . These ester intermediates 24 are hydrolyzed with two to
ten equivalents of an alkaline hydroxide such as potassium or sodium
hydroxide in aqueous methanol or ethanol to give the corresponding acids
after acidification and workup. The free acids are converted to the acid
chlorides with thionyl chloride and these acid chloride intermediates 25,
reacted with aminoaryl derivatives of formula:
Ar'--NHR.sub.a
wherein Ar' and R.sub.a are as previously defined to give compounds 27.
##STR91##
Certain of the tricyclic azepines as exemplified by compounds 33-35 are
prepared through an initial ring closure of inter-mediate acyclic
derivatives 30 followed by formation of the third ring through the use of
literature procedures (Scheme 9). Ring closure of acyclic derivatives of
structural type 30 wherein the nitrogen atom is pro-tected with a
p-toluensulfonyl group may be ring closed to give the .beta.-keto esters
31 which exist in the enol form as shown (structure 31). Decarboxylation
gives intermediates 32 which by literature procedures are converted to the
tosyl protected tricyclic azepines 33-35. The tosyl protecting group in
the derivatives, as exemplified by tricyclic azepines 33-35, can be
removed as described in the literature (P. P. Carpenter and M. Lennon, J.
Chem. Soc. Chem. Comm; 665, 1979) for sulfonamide cleavage of benzazepine
derivatives.
##STR92##
Certain intermediate azepines with a fused heterocyclic ring, as
exemplified by structure 44, which are useful in preparing the
intermediate tricyclic azepines necessary for the synthesis of the
vasopressin-oxytocin antagonists of this invention may be prepared as
illustrated in Scheme 10. Standard chemical reactions and conditions are
used to convert the azepinones of structural type 44 into the tricyclic
azepines of formulae 47-50 (via intermediates 45 and 46).
As shown in Scheme 10, expansion of a six-membered ring into a
seven-membered lactam is carried out by reaction of the ketone derivative
36with hydroxyl amine to give the oxime derivative which in most cases
exists as a mixture of syn and anti forms (structures 37 and 38). The
mixture of oximes on reaction with 4-methylbenzenesulfonyl chloride gives
either a mixture of oxime O-tosylates or in some cases a single O-tosylate
39. Heating the oxime O-tosylates with potassium acetate in a
alcohol-water mixture (such as ethanol-water or n-butanol-water) gives the
7-membered lactam derivatives 41. Reduction of the lactam with borane, or
lithium aluminium hydride (LAH) affords the fused heterocyclic azepines
42. The azepines 42may be converted to intermediates 43 and 44, which are
useful in the preparation of the novel compound of this invention. As
hereinbefore stated, the heterocyclic azepines of structural types
illustrated by formulae 45-55 may be prepared by the methods exemplified
in Scheme 10 or literature methods for ring closures to azepines.
##STR93##
Certain of the compounds of this invention wherein R.sub.a is as previously
defined are prepared by introduction of the R.sub.a group either in a
final step or in the pen-ultimate step as shown in Scheme 11. In the
derivatives 51 introduction of the R.sub.a substituent (R.sub.a not H) may
be carried out in the final step by first forming the anion of the amide
function of derivative 51 followed by the appropriate alkylation of the
nitrogen atom to give products 52. In derivatives where
protection-deprotection is needed the derivatives 51 are converted to the
protected intermediates 52a and 52b which on deprotection afford compounds
52. The R.sup.27 group may be a tertiary butoxy carbonyl group, an acetyl
group or other known amine protecting moieties. The R.sup.28 group may be
a tertiary butylcarbonyl group, an acetyl group or other known hydroxy
protecting moieties.
##STR94##
Compounds of this invention represented by the formula 59 may be prepared
from the compounds represented by those of formula 58 as shown in Scheme
12. The 6-chloro, bromo or fluoro intermediate 17 is reacted with an amino
derivative of the formula R.sub.a NH.sub.2 wherein R.sub.a is as
hereinbefore defined to give compounds of the formula 58. Reaction of the
6-aminonicotinoyl derivative 58 with an R.sup.26 -chloride wherein
R.sup.26 is defined as shown in Scheme 12 affords compounds of this
invention as exemplified by formula 59.
##STR95##
REFERENCE EXAMPLE 1
6,7-Dihydrobenzo›b!thiophen-4(5H)-one. Oxime
To a solution of 4-keto-4,5,6,7-tetrahydrothionaphthene in 260 ml of
ethanol is added 27.4 g of hydroxylamine hydrochloride. To the mixture is
added 16.5 g of sodium acetate and 66 ml of water and then the mixture is
refluxed for 3.5 hours; chilled in an ice bath and filtered. The solid is
washed with water and ethanol to give 13 g of solid which is dried at
65.degree. C. under vacuum to give 11.7 g of crystals, m.p.
124.degree.-126.degree. C. (mainly one isomer syn or anti). The filtrate
is concentrated under vacuum and extracted with 250 ml of dichloromethane.
The extract is washed with 100 ml each of water, brine and then dried
(Na.sub.2 SO.sub.4). The solvent is removed and the solid dried at
65.degree. C. under vacuum to give 32 g of crystals, m.p.
106.degree.-109.degree. C. (mainly one isomer syn or anti).
Reference Example 2
6,7-Dihydrobenzo›b!thiophen-4(5H)-one. Oxime-O-tosylate
To a stirred solution of 12.2 g of 6,7-di-hydrobenzo›b!thiophen-4(5H)-one,
oxime (mixture of isomers) in 26 ml of dry pyridine is cooled to 0.degree.
C. is added 15.3 g of p-toluenesulfonyl chloride (all at once). After 5
minutes, a solid separates and the mixture is stirred at 0.degree. C. for
1 hour. To the cold mixture is added 195 ml or 2N HCl and the mixture
filtered to give a solid which is washed with water and dried (under
vacuum) to give 21.5 g of product as crystals, m.p.
117.degree.-120.degree. C.
Reference Example 3
5,6,7,8-Tetrahydro-4H-thieno›3, 2-blazepin-5-one
A mixture of 21.45 g of 6,7-dihydrobenzo-›b!thiophen-4(5H)-one,
oxime-O-tosylate, 136.1 g of potassium acetate, 528 ml of ethanol and 904
ml of water is refluxed for 22 hours. The mixture is concentrated under
vacuum (to remove ethanol), chilled and filtered to give a solid. The
solid is washed with water, dried (in air) and recrystallized by
dissolving in hot ethyl acetate and diluting the solution with hexane.
Chilling and filtering gives 7.1 g of crystals, m.p.
128.degree.-132.degree. C.
Reference Example 4
5,6,7,8-Tetrahydro-4H-thieno›3, 2-b!azepin
(1) To a mixture of 4.54 g of lithium aluminum hydride in 400 ml of dry
tetrahydrofuran under argon is added dropwise a solution of 10.0 g of
5,6,7,8-tetrahydro-hydro-4H-thieno›3,2-b!azepin-5-one in 200 ml of
tetrahydrofuran. After the addition, the mixture is heated at
45.degree.-50.degree. C. (exothermic reaction), and cooled to room
temperature. The mixture is chilled in an ice bath (0.degree. C.) and 4.5
ml of water added dropwise over 1 hour, followed by the dropwise addition
of 4.5 ml of 2N sodium hydroxide and the dropwise addition of 14 ml of
water. The mixture is filtered through diatomaceous earth and the filter
cake washed with tetrahydrofuran. The filtrate is concentrated to give a
solid. The solid is crystallized from hexane to give 5.5 g of off-white
crystals, m.p. 66.degree.-68.degree. C.
(2) To a mixture of 21.2 g of
5,6,7,8-tetra-hydro-4H-thieno›3,2-b!azepin-5-one in 100 ml of
tetrahydrofuran under argon, chilled to 0.degree. C. is added 25.2 ml of a
10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The
solution is stirred at room temperature for 16 hours and is refluxed for 5
hours. The mixture is cooled to room temperature and 85 ml of methanol
added dropwise (exotherm). The solvent is removed and 100 ml of methanol
is added (2 times) and after each addition the solvent is removed. To the
residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the
mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted
with dichloromethane. The extract is dried (Na.sub.2 SO.sub.4) and the
solvent removed to give 15.4 g of brown solid, m.p. 55.degree.-57.degree.
C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p.
64.degree.-65.degree. C.
Reference Example 5
4-(4-Nitrobenzyl)-5,6,7,8-tetrahydro-4H-thieno›3,2-b!-azepine
To a solution of 10.71 g of 5,6,7,8-tetra-hydro-4H-thieno›3,2-b!azepine and
19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added
in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is
stirred for 3 hours at 25.degree. C. and then washed with water, sodium
bicarbonate solution, brine and dried (Na.sub.2 SO.sub.4). The solvent is
removed, the residue dried under vacuum and recrystallized by dissolving
in hot ethyl acetate and diluting with hexane. Chilling overnight and
filtering gives 16 g of light brown crystals, m.p. 141.degree.-142.degree.
C.
Reference Example 6
4-(4-Nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno›3,2-b!-azepin-8-one
To a solution of 9.0 g of
4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno›3,2-b!azepine in 713 ml of
acetone is added 6.74 g of MgSO.sub.4 and 351 ml of water followed by 8.2
g of KMnO.sub.4 and heating at 70.degree. C. for 18 hours. Another 6.24 g
of MgSO.sub.4 and 8.2 g of KMnO.sub.4 is added and heating continued at
70.degree. C. for 8 hours. An additional 6.24 g of MgSO.sub.4 and 8.2 g of
KMnO.sub.4 is added and heating continued at 70.degree. C. for 18 hours.
The reaction mixture is filtered through diatomaceous earth and the cake
washed with acetone and 500 ml of methylene chloride. The combined
filtrates are evaporated in vacuo to a residue which is washed with water
and air dried to give 5.7 g of a solid. The solid is crystallized from
ethyl acetate to give 5.1 g of off white solid, m.p.
184.degree.-186.degree. C.
Reference Example 7
4-(4-Aminobenzoyl)-4,5,6,7-tetrahydro-8H-thieno›3,2!-azepin-8-one
To a mixture of 2.0 g of
4-(4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno›3,2-b!azepin-8-one in 40
ml of glacial acetic acid is added 20 ml of 6N-hydrochloric acid. The
mixture is cooled and 3.53 g of iron powder added in portions. The mixture
is allowed to warm to room temperature and is heated at
70.degree.-80.degree. C. for 1 hour and then cooled to 0.degree. C. To
mixture is basified with 10N NaOH (pH 14) and extracted with 200 ml of
ethyl acetate. The aqueous layer is again extracted with 200 ml of ethyl
acetate and the extracts combined. The combined extract is washed with 100
ml each of H.sub.2 O and brine and dried (Na.sub.2 SO.sub.4). The extract
is filtered through a thin pad of hydrous magnesium silicate and the
filtrate concentrated to give a solid which is crystallized from ethyl
acetate-hexane to give 1.24 g of crystals, m.p. 216.degree.-218.degree. C.
Reference Example 8
2-Chloro-4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno›3,2-b!azepine
A solution of 6.04 g of
4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno›3,2-b!azepine in 40 ml of
tetrahydrofuran is cooled to 0.degree. C. and 5.34 g of
N-chlorosuccinimide added in portions. After the addition, the mixture is
heated at 70.degree. C. overnight. The mixture is concentrated, diluted
with 300 ml of dichloromethane and the mixture washed with 100 ml each of
saturated K.sub.2 CO.sub.3 solution, H.sub.2 O, 1N HCl and brine. The
organic layer is dried (Na.sub.2 SO.sub.4) and filtered through a thin pad
of hydrous magnesium silicate. The filtrate is concentrated and the
residue chromatographed by HPLC on silica gel (2-columns) with a
Waters-Prep-500 instrument and the solvent system ethyl
acetate-dichloromethane (1:1) containing 2% diethylether. The middle cuts
are combined and concentrated to give 0.135 g of
2,3-di-chloro-4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno-›3,2-b!azepi
ne, m.p. 140.degree.-142.degree. C. The latter cuts are combined,
concentrated and the residue crystallized from ethyl acetate-hexane to
give 2.8 g of crystals, 119.degree.-120.degree. C.
Reference Example 9
2-Chloro-4-(4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno›3,2b!azepin-8-one
To a stirred solution of 0.336 g of
2-chloro-4-(4-nitrobenzoyl)-4,5,6,7-tetrahydro-4H-thieno›3,2-b!azepine in
36 ml of acetone-water (2:1) is added 0.21 g of anhydrous magnesium
sulfate and 0.275 g of potassium permanganate. The mixture is heated at
70.degree. C. overnight. An additional 0.275 g of potassium permanganate
and 0.21 g of magnesium sulfate is added and the mixture heated at
70.degree. C. for 6 hours. An additional 0.275 g of potassium permanganate
and 0.21 g of magnesium sulfate is added and the mixture stirred and
heated at 70.degree. C. for 24 hours. The hot mixture is filtered and the
filtrate evaporated. The residue is heated in a few ml of ethyl acetate,
cooled and filtered to give 0.20 g of product as a solid. The reaction is
repeated on 10 times the scale to give 1.3 g of off-white crystals, m.p.
165.degree.-168.degree. C.
Reference Example 10
Methyl 4-›2-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl) ethyl!benzoate
A 0.876 g sample of 60% sodium hydride in oil is washed with hexane
followed by the addition of 60 ml of dry N,N-dimethylformamide. The
reaction mixture is stirred for 1 hour under argon at room temperature
after the addition of 4.73 g of
.alpha.-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture
is added 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continued
for 3 hours. Several drops of acetic acid is added to ice water and the
reaction quenched. The pH is 3-4 and saturated NaHCO.sub.3 added to adjust
the pH to 6-7. Upon cooling a solid forms which is filtered, washed with
water and dried to give 5.92 g of yellow solid. Crystallization from
methylene chloride-hexane gives 2.10 g of the desired product as a
crystalline solid, m.p. 116.degree.-118.degree. C.
Reference Example 11
Methyl 4-›2-(2-chlorophenyl)-2-oxoethyl!benzoate
A mixture of 1.0 g of
methyl›4-(2-chloro-phenyl)-2-cyano-2-(4-morpholinyl)ethyl!benzoate and 14
ml of acetic acid and 6 ml of water is heated at reflux for 20 minutes
then poured over crushed ice. After stirring for 15 minutes, the resulting
solid is collected, washed with water and air dried to give 0.63 g of tan
solid, m.p. 40.degree.-42.degree. C.
Reference Example 12
4-›2-(2-Chlorophenyl)-2-oxoethyl!benzoic acid
A mixture of 18.78 g of methyl 4-›2-(2-chlorophenyl)-2-oxoethyl!benzoate in
288.8 ml of CH.sub.3 OH, 72.2 ml of water and 5.2 g of NaOH is refluxed
for 3 hours then acidified with 2N citric acid. The reaction mixture is
evaporated in vacuo to remove the CH.sub.3 OH. The aqueous phase is
extracted with CH.sub.2 Cl.sub.2 and acidified with 1N HCl. The resulting
solid is collected and dried under vacuum to give 17.27 g of the desired
product, m.p. 168.degree.-172.degree. C.
Reference Example 13
Methyl 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylate
To a solution of 2.11 g of
4-oxo-4,5,6,7-tetrahydrobenzo›b!furan-3-carboxylic acid in 100 ml of
methanol is added 202 mg of p-toluenesulfonic acid hydrate and the mixture
heated at reflux for 24 hours. The reaction mixture is cooled to room
temperature and the methanol concentrated in vacuo to a residue. The
residue is dissolved in 100 ml of ethyl acetate and washed with 30 ml of
saturated sodium bicarbonate and 30 ml of brine. The organic layer is
dried with Na.sub.2 SO.sub.4, filtered and the filtrate concentrated in
vacuo to a residue which is crystallized from ethyl acetate-hexane to give
1.75 g of the desired product as a white crystalline solid, m.p.
100.degree.-102.degree. C.
Reference Example 14
Methyl 5,6,7,8-tetrahydro-5-oxo-4H-furo›3,2-b!azepine-3-carboxylate
To a mixture of 1.0 g of methyl
4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylate and 502 mg of sodium
azide in 5 ml of chloroform is added dropwise at 32.degree.-36.degree. C.
under argon 1.4 ml of sulfuric acid. The reaction mixture is stirred at
room temperature for 24 hours. The reaction mixture is diluted with 14 ml
of water and rendered alkaline with NH.sub.4 OH and extracted with
chloroform. The separated organic layer is washed with water, brine and
dried with Na.sub.2 SO.sub.4 and concentrated in vacuo to give 1.0 g of
the desired product as a white solid.
Reference Example 15
(E)
4,5,6,7-Tetrahydro-4-›››(4methylphenyl)-sulfonyl!oxy!imino!-3-benzofuranca
rboxylic acid
To a partial solution of 2.8 g of
(E)-4,5,6,7-tetrahydro-4-(hydroxyimino)-3-benzofurancarboxylic acid in 7
ml of pyridine is added portionwise at 0.degree.C., 3.01 g of p-toluene
sulfonyl chloride under argon. The mixture is stirred for 1 hour then
diluted with 40 ml of cold 1N HCl, filtered, washed with water and dried
with Na.sub.2 SO.sub.4. The filtrate is concentrated in vacuo to give 4.78
g of the desired product as an off-white solid, m.p.
155.degree.-165.degree. C.
Reference Example 16
5,6,7,8-Tetrahydro-5-oxo-4H-furo›3,2-b!azepine-3-carboxylic acid
A mixture of 1.0 g of
(E)-4,5,6,7-tetrahydro-4-›››(4-methylphenyl)sulfonyl!oxy!imino!-3-benzofur
ancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml
of water is heated at reflux for 48 hours. The reaction mixture is
concentrated in vacuo, 80 ml of methylene chloride added and the separated
organic layer washed with water, brine and dried with Na.sub.2 SO.sub.4.
The organic layer is concentrated in vacuo to a solid which is purified by
chromatography on a preparative silica gel plate by elution with 0.5%
acetic acid in ethyl acetate. The eluted band is washed with 1% acetic
acid in ethyl acetate. The organic layer is dried with Na.sub.2 SO.sub.4
and concentrated in vacuo to give 200 mg of off-white solid which is
crystallized from ethyl acetate-hexane to give 165 mg of the desired
product as a white solid.
Reference Example 17
(E) and (Z)-4,5,6,7-Tetrahydro-4-(hydroxyimino)-3-benzofurancarboxylic acid
To a solution of 30.0 g of 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylic
acid in 225 ml of ethanol is added 22.97 g of hydroxylamine hydrochloride,
followed by 18.10 g of sodium acetate and 55 ml of water. The reaction
mixture is heated at reflux for 2.5 hours and concentrated in vacuo to a
residue which is diluted with 600 ml of ethyl acetate, washed with
2.times.200 ml of water, brine and dried over Na.sub.2 SO.sub.4. The
organic layer is concentrated in vacuo to a residue which is dried under
vacuum to give 31.0 g of the desired product as a solid.
Reference Example 18
(E) and (Z)-6,7-Dihydro-4-(5H)benxofuranone,
O-›(4-methylphenyl)sulfonyl!oxime
To a partial solution of 28.0 g of (E) and
(Z)-4,5,6,7-tetrahydro-4-(hydroxyimino)benzofuran in 54 ml of pyridine is
added portionwise at 0.degree. C., 38.8 g of p-toluene sulfonyl chloride
under argon. The mixture is stirred for 1 hour then diluted with 600 ml of
ethyl acetate and 400 ml of cold 2N HCl. The organic layer is washed with
200 ml of water and 200 ml of brine, and dried with Na.sub.2 SO.sub.4. The
filtrate is concentrated in vacuo to give 50 g of the desired product as a
solid. Crystallization from ethyl alcohol by allowing to stand at room
temperature gives 19.9 g of off-white needles, m.p.
123.degree.-125.degree. C. The filtrate is allowed to stand and the
crystals collected and dried to give 10.0 g of the desired product as an
off-white solid, 83.degree.-85.degree. C.
Reference Example 19
4-(2-Chloro-4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno›3,2-b!azepine
To a solution of 15.0 g of 5,6,7,8-tetrahydro-4H-thieno›3,2-b!azepine in
150 ml of dichloromethane cooled to 0.degree. C. is added 27.2 ml of
triethylamine. After stirring 5 minutes, a solution of 28.0 g of
2-chloro-4-nitrobenzoyl chloride in 140 ml of dichloromethane is added
slowly. The solution is stirred at room temperature overnight, diluted
with 450 ml of dichloromethane and the solution washed with 200 ml each of
water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer
is dried over Na.sub.2 So.sub.4, filtered through a thin pad of hydrated
magnesium silicate and the filtrate concentrated under vacuum. The residue
is crystallized from ethyl acetate to give 24.3 g of off-white crystals,
m.p. 131.degree.-134.degree. C.
Reference Example 20
4-(2-Chloro-4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno›3o2-b!azepine-8-on
e
To a solution of 2.02 g of
4-(2-chloro-4-nitrobenzoyl)-4,5,6,7,8-tetrahydro-4H-thieno›3,2-b!-azepine
in 144 ml of acetone is added 1.56 g of magnesium sulfate, 72 ml of water
and 1.89 g of potassium permanganate. The mixture is stirred and heated at
70.degree.-75.degree. C. for 4 hours. An additional amount of magnesium
sulfate (1.56 g) and potassium permanganate (1.89 g) is added and the
mixture stirred and heated at 75.degree. C. for 16 hours. Magnesium
sulfate (1.56 g) and potassium permanganate (1.89 g) are added and the
mixture stirred and heated at 75.degree. C. for 5 hours. The mixture is
filtered through diatomaceous earth and the filter cake washed with
acetone and dichloromethane The filtrate is concentrated and the residue
(1.4 g) is heated with ethyl acetate, the mixture (with insoluble solid)
cooled and filtered to give 1.0 g of product as a solid. The solid is
washed with water and dried to give crystals, m.p. 180.degree.-185.degree.
C.
Reference Example 21
5-Fluoro-2-methylbenzoyl chloride
A mixture of 8.0 g of 5-fluoro-2-methylbenzoic acid and 52 ml of thionyl
chloride is heated on a steam bath for 1 hour. The volatiles are removed
under vacuum and two times 50 ml of toluene is added and the solvent
removed under vacuum to give 8.5 g of product as a gum.
Reference Example 22
2-Chloro-5-(methylthio)benzoyl chloride
A mixture of 2.03 g of 2-chloro-5-(methylthio)benzoic acid and 10 ml of
thionyl chloride is heated on a steam bath for 1 hour. The volatiles are
removed under vacuum and 20 ml of toluene added and removed under vacuum
(2 times) to give 2.2 g of brown needles.
Reference Example 23
2-Chloro-4-nitrobenzoyl chloride
As described for Reference Example 21, 25 g of 2-chloro-4-nitrobenzoic acid
is reacted with thionyl chloride (124 ml) to give the product (27.0 g) as
a brown oil.
Reference Example 24
2-Chloro-5-nitrobenzoyl chloride
As described for Reference Example 21, 5.0 g of 2-chloro-5-nitrobenzoic
acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the
product as an off-white solid.
Reference Example 25
2,3-Dimethylbenzoyl chloride
As described for Reference Example 21, 3.0 g of 2,3-dimethylbenzoic acid is
reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a
colorless oil.
Reference Example 26
2-Chlorobenzoyl chloride
As described for Reference Example 21, 3.13 g of 2-chlorobenzoic acid is
reacted with 40 ml of thionyl chloride to give 3.32 of product as an
off-white semi solid.
Reference Example 27
4-›(2-Methylbenzoyl)amino!benzoic acid
A mixture of 43.42 g (0.26 mol) of ethyl 4-aminobenzoate and 40.8 g (0.26
mol) of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in
an ice bath and 26.56 g (0.26 mol) of triethylamine is added dropwise.
After the addition, the solution is stirred at room temperature overnight.
The mixture is poured into water and the organic layer separated. The
organic layer is washed with water, 1N HCl, 1M NaHCO.sub.3 and dried
(Na.sub.2 SO.sub.4). The solvent is removed and the solid slurried with
ethyl acetate and filtered to give 57 g of ethyl
4-›(2-methylbenzoyl)amino!benzoate as crystals, m.p.
110.degree.-115.degree. C.
A mixture of 50.7 g (0.20 mol) of the preceding compound, 280 ml of ethanol
and 55 ml of 10N NaOH is refluxed for 5 minutes. The mixture is cooled to
room temperature, diluted with 200 ml of water and acidified with
concentrated hydrochloric acid (pH 1-2). The mixture is filtered and the
solid washed with water and dried to give 51 g of product as white
crystals, m.p. 270.degree.-275.degree. C.
Reference Example 28
4-›(2-Methylbenzoyl)amino!benzoyl chloride
A mixture of 10.3 g of 4-›(2-methylbenzoyl)-amino!benzoic acid and 32 ml of
thionyl chloride is refluxed for 1.5 hours. The solution is concentrated
under vacuum. Toluene is added and the solvent removed under vacuum.
Toluene is added and the mixture chilled and filtered to give a yellow
solid, m.p. 135.degree.-141.degree. C.
Reference Example 29
4-›(2,6-Dimethoxybenzoyl)amino!benzoic acid
A mixture of 2 g (10 mmol) of 2,6-dimethoxybenzoyl chloride, 1.65 g (10
mmol) of ethyl 4-aminobenzoate, 1.11 g of triethylamine and 61 mg of
4-dimethylaminopyridine in 10 ml of dichloromethane is refluxed for 20
hours. The mixture is diluted with water and the organic layer separated.
The organic layer is washed with water, 1N HCl, 1N Na.sub.2 CO.sub.3,
brine and dried (Na.sub.2 SO.sub.4). The solvent is removed to give a
solid which is crystallized from ethyl acetate to give 1.22 g of ethyl
4-›(2,6-dimethoxybenzoyl)amino!benzoate as crystals, m.p.
183.degree.-185.degree. C.
A mixture of 3.88 g (11.79 mmol) of the preceding compound, 17.3 ml of 2N
NaOH and 20 ml of methanol is stirred at room temperature overnight.
Methanol (30 ml) and water (10 ml) are added and the solution refluxed for
1/2 hour. The solvents are removed under vacuum and the residual solid
triturated with ether and the ether decanted. The solid is dissolved in 30
ml of water and acidified with 2N HCl (pH 3). The mixture is filtered, the
solid washed with water and dried at 60.degree. C under vacuum to give 3.0
g of solid, m.p. 236.degree.-240.degree. C.
Reference Example 30
Ethyl 4-›(4-pyridinylcarbonyl)amino!benzoic acid
To a cooled mixture of 1.78 g (0.01 mol) of isoniconinoyl chloride
hydrochloride in 5 ml of di-chloromethane is added 2.52 g (0.025 mol) of
triethylamine. To the solution is added a solution of 1.65 g of ethyl
4-aminobenzoate in 5 ml of dichloromethane. After stirring at room
temperature overnight, 50 mg of 4-di-methylaminopyridine is added and the
mixture is refluxed for 24 hours. The mixture is poured into water and
filtered to give 3.4 g of brown solid. A 0.50 g sample is triturated with
ethyl acetate to give 0.37 g of ethyl
4-›(4-pyridinylcarbonyl)amino!benzoate as yellow crystals, m.p.
143.degree.-145.degree. C.
Reference Example 31
2-Methylfurane-3-carbonyl chloride
A mixture of 4.0 g of methyl-2-methylfurane-3-carboxylate, 30 ml of 2N NaOH
and 15 ml methanol is refluxed for 1.5 hours. The solvent is removed under
vacuum to give a solid. The solid is extracted with dichloromethane
(discarded). The solid is dissolved in water and the solution acidified
with 2N citric acid to give a solid. The solid is washed with water and
dried to give crystals 1.05 g of crystals of 2-methylfuran-3-carboxylic
acid. The preceding compound (0.95 g) and 3 ml of thionyl chloride is
refluxed for 1 hour. The solvent is removed, toluene added (20 ml, three
times) and the solvent removed to give the product as an oil.
Reference Example 32
4-›N-Methyl-N-(2-methylbenzoyl)amino!benzoic acid
A sample of 1.51 g of sodium hydride) 60% in oil) is washed with hexane
under argon to remove the oil. To the washed sodium hydride is added 5 ml
of N,N-dimethylformamide. To this mixture is added dropwise a solution of
8.69 g of ethyl 4-›(2-methylbenzoyl)amino!-benzoate in 20 ml of
dimethylformamide. The mixture is stirred at room temperature for 0.5 hour
and then 5.23 g of methyl iodide is added. The mixture is stirred at room
temperature for 16 hours. The mixture is diluted with water and extracted
with dichloromethane. The extract is dried (Na.sub.2 SO.sub.4),
concentrated to reduce the volume and the solution filtered through a thin
pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo
to give 11 g of an oil (1:1 mixture of product and N,N-dimethylformamide).
The preceding product, ethyl
4-›N-methyl-N-(2-methylbenzoyl)amino!-benzoate, (11 g) is dissolved in 30
ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2
hours and the solvent removed. The residue is extracted with ether
(discard) and the remaining residue dissolved in 50 ml of water. The basic
solution is acidified with 2N citric acid and the solid filtered off and
washed with water. The product is air dried to give 6.72 g of crystals,
m.p. 187.degree.-190.degree. C.
Reference Example 33
4-›N-Methyl-N-›(2-methylbenzoyl)amino!benzoyl chloride
A solution of 6.72 g of 4-›N-methyl-N-(2-methylbenzoyl)amino!benzoic acid
in 20 ml of thionyl chloride is refluxed for one hour. The volatiles are
removed in vacuo. Toluene is added to the residue and then the toluene
removed in vacuo (repeated several times) to give the 7.3 g of product as
a brown oil.
As described for Reference Example 32, but substituting the appropriate
ethyl 4-›(N-aroyl)amino!-benzoate, the following compounds are prepared.
Reference Example 34
4-›N-Methyl-N-(2-chlorobenzoyl)amino!benzoic acid
Reference Example 35
N-›N-Methyl-N-(2,5-dichlorobenzoyl)amino!benzoic acid
Reference Example 36
N-›N-Methyl-N-(2,4-dichlorobenzoyl)amino!benzoic acid
Reference Example 37
4-›N-Methyl-N-(2-chloro-4-methylbenzoyl)amino!benzoic acid
Reference Example 38
4-›N-methyl-N-(2-methyl-4-chlorobenzoyl)amino!benzoic acid
Reference Example 39
4-›N-Methyl-N-(2,4-dimethylbenzoyl)amino!benzoic acid
Reference Example 40
4-›N-Methyl-N-(2,3-dimethylbenzoyl)amino!benzoic acid
Reference Example 41
4-›N-Methyl-N-(2-methoxybenzoyl)amino!benzoic acid
Reference Example 42
4-›N-Methyl-N-(2-trifluoromethoxybenzoyl)amino!benzoic acid
Reference Example 43
4-›N-Methyl-N-(2,4-dimethoxybenzoyl)amino!benzoic acid
Reference Example 44
4-›N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino!benzoic acid
Reference Example 45
4-›N-Methyl-N-(2-methylthiobenzoyl)amino!benzoic acid
Reference Example 46
4-›N-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino!benzoic acid
Reference Example 47
4-›N-Methyl-N-(3-methylthiophene-2-ylcarbony)amino!benzoic acid
Reference Example 48
4-›N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino!benzoic acid
Reference Example 49
4-›N-Methyl-N-(3-methylfuran-2-ylcarbonyl!amino!benzoic acid
Reference Example 50
4-›N-Methyl-N-(phenylacetyl)amino!benzoic acid
Reference Example 51
4-›N-Methyl-N-(2-chlorophenylacetyl)amino!benzoic acid
Reference Example 52
4-›N-Methyl-N-(2-methoxyphenylacetyl)amino!benzoic acid
Reference Example 53
4-›N-Methyl-N-(2-methylphenylacetyl)amino!benzoic acid
Reference Example 54
4-›N-Methyl-N-(cyclohexylcarbonyl)amino!benzoic acid
Reference Example 55
4-›N-Methyl-N-(3-cyclohexenecarbonyl)amino!benzoic acid
Reference Example 56
4-›N-Methyl-N-(cyclohexylacetyl)amino!benzoic acid
Reference Example 57
7,8-Dihydro-5-(6H)quinolinone
A mixture of 57.93 g of 3-amino-2-cyclohexene-1-one, 76.8 g of
3-(dimethylamino)acrotein, 62.5 ml of glacial acetic acid and 270 ml of
toluene is refluxed under argon for 16 hours and concentrated under vacuum
to dryness. Toluene (200 ml) is added and the solvent removed under
vacuum. To the residue is added one liter of dichloromethane and then 200
ml of saturated NaHCO.sub.3 slowly added and solid NaHCO.sub.3 added to
bring the pH to 8. The mixture is filtered and the CH.sub.2 Cl.sub.2 layer
separated. The CH.sub.2 Cl.sub.2 layer is passed through a thin pad of
hydrous magnesium silicate and the filtrate concentrated to dryness. The
residual black oil is extracted with hot hexane and the hexane decanted.
This process is repeated until no more product extracted into the hexane.
The hexane extracts are combined and the solvent removed to give 17.3 g of
product as an oil.
Reference Example 64
7,8-Dihydro-5(6H)quinolinone, oxime
To a solution of 3.78 g of 7,8-dihydro-5(6H)quinolone in 20 ml of ethanol
is added 2.68 g of hydroxylamine, hydrochloride, 3.23 g of sodium acetate
and 5 ml of water. The mixture is refluxed under argon for 4.5 hours,
cooled and filtered. The solid is washed with 30 ml of ethanol-water (1:1)
and dried under vacuum to give 3.58 g of solid, m.p.
232.degree.-236.degree. C. Recrystallization from ethanol gives crystals,
m.p. 234.degree.-236.degree. C.
Reference Example 65
7,8-Dihydro-5 (6H)quinolinone, O-›(4-methylphenyl) sulfonyl!oxime
To a mixture of 2.30 g of 7,8-dihydro-5(6H)-quinolinone, oxime, 3.59 g of
4-methylphenylsulfonyl chloride in 32 ml of acetone is added a solution of
0.84 g of potassium hydroxide in 10 ml of water. The mixture is refluxed
for 0.5 hour under argon and the volatiles removed under vacuum. Water is
added to the residue and the mixture is filtered and the solid washed with
water and 1N NaHCO.sub.3. The solid is dissolved in dichloromethane, dried
and the solvent removed to give 3.83 g of solid. Recrystallization from
diethyl ether gives crystals, m.p. 102.degree.-104.degree. C.
Reference Example 66
5,7,8,9-Tetrahydro-6H-pyrido›3,2-b!azepin-6-one
A mixture of 8.26 g of 7,8-dihydro-5(6H)-quinolinone,
O-›(4-methylphenyl)sulfonyl!oxime, 54.63 g of potassium acetate, 193 ml of
ethanol and 354 ml of water is refluxed for 20 hours. The mixture is
concentrated under vacuum to remove volatiles and the aqueous residue
(contains solid) is added chloroform. The mixture is filtered through
diatomaceous earth, the filter pad washed with chloroform and the filtrate
concentrated to dryness. The residual solid is recrystallized from acetone
to give 2.81 g of crystals, m.p. 156.degree.-159.degree. C.
Reference Example 67
6,7,8,9-Tetrahydro-5H-pyrido›3,2-b!azepine
A mixture of 1.56 g of 5,7,8,9-tetrahydro-6H-pyrido›3,2-b!azepine-6-one,
3.31 g of lithium aluminum hydride in 40 ml of tetrahydrofuran is refluxed
for 4 hours. The mixture is cooled (0.degree. C.) and 25 ml of methanol is
added dropwise. The mixture is filtered through diatomaceous earth, the
filter cake washed with tetrahydrofuran and the filtrate concentrated to
dryness under vacuum. Water (50 ml) is added to the residue and the
mixture extracted with diethyl ether. The extract is dried (Na.sub.2
SO.sub.4) and filtered through a thin pad of hydrous magnesium silicate
(pad washed with) diethyl ether. The filtrate is concentrated under vacuum
to give 1.01 g of crystals, m.p. 70.degree.-71.degree. C.
Reference Example 68
6,7,8,9-Tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido›3,2-b!azepine
To a mixture of 2.90 g of 6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine, 2.37
g of triethylamine in 40 ml of dichloromethane is added 5.16 g of
2-chloro-4-nitrobenzoyl chloride in 50 ml of dichloromethane. The mixture
is stirred at room temperature under argon for 3 hours and then poured
into water. The organic layer is separated and washed with 1N NaHCO.sub.3,
H.sub.2 O, brine and dried (Na.sub.2 SO.sub.4). The solution is filtered
through a thin pad of hydrous magnesium silicate, the pad washed with
CH.sub.2 Cl.sub.2 and ethyl acetate and the filtrate concentrated to
dryness. The residual solid (7.13 g) is triturated with ethyl acetate to
give 4.41 g of off-white crystals, m.p. 143.degree.-145.degree. C.
Reference Example 69
6,7,8,9-Tetrahydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrido›3,2-b!azipine
A mixture of 3.31 g of
6,7,8,9-tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido›3,2-b!azepine and
6.78 g of stannus chloride dihydrate (SnCl.sub.2.2H.sub.2 O) in 200 ml of
methanol is refluxed for 2 hours under argon. The solvent is removed under
vacuum and 5 ml of saturated NaHCO.sub.3 solution and solid NaHCO.sub.3
added to bring the pH to 7. The mixture is extracted with ethyl acetate,
the extract filtered through diatomaceous earth and the filtrate washed
with saturated NaHCO.sub.3, H.sub.2 O, brine and dried (Na.sub.2
SO.sub.4). The filtrate is passed through a thin pad of hydrous magnesium
silicate and the filtrate concentrated to dryness to give 2.58 g of an
amorphous solid. Anal. Calc'd for C.sub.16 H.sub.16 ClN.sub.3 O;
C,59.9;H,5.7; N,13.1;Cl, 11.1 Found: C,60.5; H,5.0; N,12.9; Cl, 11.6.
Reference Example 70
Methyl 6-aminopyridine-3-carboxylate
Dry methanol (400 ml) is cooled in an ice bath and HCl gas is bubbled into
the mixture for 25 minutes. To the MeOH-HCl is added 30 g of
6-aminopyridine-3-carboxylic acid and then the mixture is stirred and
heated at 90.degree. C. for 2 hours (all the solid dissolved). The solvent
is removed under vacuum and the residual solid dissolved in 100 ml of
water. The acidic solution is neutralized with saturated sodium
bicarbonate (solid separated) and the mixture chilled and filtered to give
30 g of white crystals, m.p. 150.degree.-154.degree. C.
Reference Example 71
6-›(5-fluoro-2-methylbenzoyl) amino!pyridine-3-carboxylic acid
To a mixture of 4.5 g of methyl 6-amino-pyridine-3-carboxylate and 5.53 ml
of triethylamine in 40 ml of dichloromethane (cooled in an ice bath) is
added 6.38 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of
dichloromethane. The mixture is stirred at room temperature under argon
for 18 hours and an additional 3.4 g of 5-fluoro-2-methylbenzoyl chloride
added. After stirring at room temperature for 3 hours, the mixture is
filtered to give 3.0 g of methyl
6-››bis(5-fluoro-2-methylbenzoyl)!amino!pyridine-3-carboxylate. The
filtrate is concentrated to dryness and the residue triturated with hexane
and ethyl acetate to give an additional 9.0 g of bis acylated compound.
A mixture of 12.0 g of methyl
6-››bis(5-fluoro-2-methylbenzoyl)!amino!pyridine-3-carboxylate, 60 ml of
methanol-tetrahydrofuran (1:1) and 23 ml of 5 N NaOH is stirred at room
temperature for 16 hours. The mixture is concentrated under vacuum,
diluted with 25 ml of water, cooled and acidified with 1N HCl. The mixture
is filtered and the solid washed with water to give 6.3 g of the product
as a white solid.
As described for Reference Example 71, but substituting the appropriate
aroyl chloride, heteroaroyl chloride, cycloalkanoyl chlorides,
phenylacetylchlorides and related appropriate acid chlorides, the
following 6-›(aroylamino!pyridine-3-carboxylic acids,
6-›(heteroaroyl)amino!pyridine-3-carboxylic acids and related
6-›(acylated)amino!pyridine-3-carboxylic acids are prepared.
Reference Example 72
6-›(2-Methyl-2-thienylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 73
6-›(3-Methyl-3-thienylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 74
6-›(3-Methyl-2-furanylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 75
6-›(2-Methyl-3-furanylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 76
6-›(3-fluoro-2-methylbenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 77
6-›(2-Methylbenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 78
6-›(2-chlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 79
6-›(2-Fluorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 80
6-›(2-Chloro-4-fluorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 81
6-›(2,4-Dichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 82
6-›(4-Chloro-2-fluorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 83
6-›(3,4,5-Trimethoxybenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 84
6-›(2,4-Difluorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 85
6-›(2-Bromobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 86
6-›(2-Chloro-4-nitrobenzyl)amino!pyridine-3-carboxylic acid
Reference Example 87
6-›(Tetrahydrofuranyl-2-carbonyl)amino!pyridine-3-carboxylic acid
Reference Example 88
6-›(Tetrahydrothienyl-2-carbonyl)amino!pyridine-3-carboxylic acid
Reference Example 89
6-›(Cyclohexylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 90
6-›(cyclohex-3-enecarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 91
6-›(5-Fluoro-2-methylbenzeneacetyl)amino!pyridine-3-carboxylic acid
Reference Example 92
6-›(2-Chlorobenzeneacetyl)amino!pyridine-3-carboxylic acid
Reference Example 93
6-›(cyclopentylcarbonyl)amino!pyridine-3-carboxylic acid
Reference Example 94
6-›(cyclohexylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 95
6-›(3-Methyl-2-thienylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 96
6-›(2-Methyl-3-thienylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 97
6-›(3-Methyl-2-furanylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 98
6-›(2-Methyl-3-furanylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 99
6-›(3-Methyl-2-tetrahydrothienylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 100
6-›(2-Methyl-3-tetrahydrothienylacetyl)amino!pyridine-3-carboxylic acid
Reference Example 101
6-›(2,5-Dichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 102
6-›(3,5-Dichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 103
6-›(2-Methyl-4-chlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 104
6-›(2,3-Dimethylbenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 105
6-›(2-Methoxybenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 106
6-›(2-Trifluoromethoxybenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 107
6-›(4-Chloro-2-methoxybenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 108
6-››2-(Trifluoromethyl)benzoyl!amino!pyridine-3-carboxylic acid
Reference Example 109
6-›(2,6-Dichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 110
6-›(2,6-Dimethylbenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 111
6-›(2-Methylthiobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 112
6-›(4-Fluoro-2-(trifluoromethyl)benzoyl)amino!pyridine-3-carboxylic acid
Reference Example 113
6-›(2,3-Dichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 114
6-›(4-Fluoro-2-methylbenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 115
6-›(2,3,5-Trichlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 116
6-›(5-Fluoro-2-chlorobenzoyl)amino!pyridine-3-carboxylic acid
Reference Example 117
6-›(2-Fluoro-5-(trifluoromethyl)benzoyl)amino!pyridine-3-carboxylic acid
Reference Example 118
6-›(5-Fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride
A mixture of 6.2 g of
6-›(5-fluoro-2-methyl-benzoyl)amino!pyridine-3-carboxylic acid and 23 ml
of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thionyl
chloride is added and the mixture refluxed for 0.5 hour. The mixture is
concentrated to dryness under vacuum and 30 ml of toluene added to the
residue. The toluene is removed under vacuum and the process (add toluene
and remove) is repeated to give 7.7 g of crude product as a solid.
As described for Reference Example 118, the following
6-(acyl)amino)pyridine-3-carbonyl chlorides are prepared.
Reference Example 119
6-›(3-Methyl-2-thienylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 120
6-›(2-Methyl-3-thienylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 121
6-›(3-Methyl-2-furanylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 122
6-›(2-Methyl-3-furanylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 123
6-›(3-Fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 124
6-›(2-Methylbenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 125
6-›(2-Chlorobenzoyl)amino!pyridine-3-carbonyl chloride, white crystals
Reference Example 126
6-›(2-Fluorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 127
6-›(2-Chloro-4-fluorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 128
6-›(2,4-Dichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 129
6-›(4-Chloro-2-fluorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 130
6-›(3,4,5-Trimethoxybenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 131
6-›(2,4-Difluorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 132
6-›(2-Bromobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 133
6-›(2-Chloro-4-nitrobenzyl)amino!pyridine-3-carbonyl chloride
Reference Example 134
6-›(Tetrahydrofuranyl-2-carbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 135
6-›(Tetrahydrothienyl-2-carbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 136
6-›(Cyclohexylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 137
6-›(Cyclohex-3-enecarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 138
6-›(2-Methylbenzeneacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 139
6-›(2-Chlorobenzeneacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 140
6-›(Cyclopentylcarbonyl)amino!pyridine-3-carbonyl chloride
Reference Example 141
6-›(Cyclohexylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 142
6-›(3-Methyl-2-thienylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 143
6-›(2-Methyl-3-thienylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 144
6-›(3-Methyl-2-furanylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 145
6-›(2-Methyl-3-furanylacetyl!amino!pyridine-3-carbonyl chloride
Reference Example 146
6-›(2-Methyl-5-fluorobenzeneacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 147
6-›(3-Methyl-2-tetrahydrothienylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 148
6-›(2-Methyl-3-tetrahydrothienylacetyl)amino!pyridine-3-carbonyl chloride
Reference Example 149
6-›(2,5-Dichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 150
6-›(3,5-Dichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 151
6-›(2-Methyl-4-chlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 152
6-›(2,3-Dimethylbenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 153
6-›(2-Methoxybenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 154
6-›(2-Trifluoromethoxybenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 155
6-›(4-Chloro-2-methoxybenzoyl)!amino!pyridine-3-carbonyl chloride
Reference Example 156
6-››2-(Trifluoromethyl)benzoyl!amino!pyridine-3-carbonyl chloride
Reference Example 157
6-›(2,6-Dichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 158
6-›(2.6-Dimethylbenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 159
6-›(2-Methylthiobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 160
6-›(4-Fluoro-2-(trifluoromethyl)benzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 161
6-›(2,3-Dichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 162
6-›(4-Fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 163
6-›(2,3,5-Trichlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 164
6-›(5-Fluoro-2-chlorobenzoyl)amino!pyridine-3-carbonyl chloride
Reference Example 165
6-›(2-Fluoro-5-(trifluoromethyl)benzoyl)amino!pyridine-3-carbonyl chloride
As described for Reference Example 71, the following bis acylated products
(Table A) are prepared and purified by silica gel chromatography. These
compounds are then hydrolysed to the acids as described in Example 71
(Table B).
TABLE A
______________________________________
##STR96##
Ref
Ex No. R.sub.1 R.sub.2 R.sub.3
R.sub.4
X M.sup.+
______________________________________
166 CH.sub.3
H H H H 388
167 CH.sub.3
H H F H 424
168 CH.sub.3
F H H H 426
169 H OCH.sub.3
OCH.sub.3
OCH.sub.3
H 540
170 Cl H H H H 430
171 F H F H H 396
172 Br H H H H 520
173 Cl H F H H 412
174 Ph H H H H 512
175 Cl H H Br H 474
176 CH.sub.3
H H F Br
177 CH.sub.3
H H H Br 468
______________________________________
M.sup.+ is molecular ion found from FAB mass spectrum
TABLE B
______________________________________
##STR97##
Ref
Ex No. R.sub.1 R.sub.2 R.sub.3
R.sub.4
X M.sup.+
______________________________________
178 CH.sub.3
H H H H 256
179 CH.sub.3
H H F H 274
180 CH.sub.3
F H H H 274
181 H OCH.sub.3
OCH.sub.3
OCH.sub.3
H 332
182 Cl H H H H 276
183 F H F H H 278
184 Br H H H H 322
185 Cl H F H H 294
186 Ph H H H H 318
187 Cl H H Br H 356
188 CH.sub.3
H H F Cl
189 CH.sub.3
H H H Br 336
______________________________________
M.sup.+ is molecular ion found from FAB mass spectrum.
Reference Example 190
6-Amino-5-bromopyridine-3-carboxylic acid
To a stirred solution of 6-aminonicotinic acid (13.8 g, 0.1 mole) in
glacial acetic acid (100 ml), bromine (16 g, 5 ml, 0.1 mole) in acetic
acid (20 ml) is added slowly. The reaction mixture is stirred for 8 hours
at room temperature and the acetic acid is removed under reduced pressure.
The yellow solid residue is dissolved in water and carefully neutralized
with 30% NH.sub.4 OH. The separated solid is filtered and washed with
water to give 18 g of solid; mass spectrum: 218 (M.sup.+).
Reference Example 191
Methyl 6-amino-5-bromopyridine-3-carboxylate
6-Amino-5-bromopyridine-3-carboxylic acid (10 g, 50 mmol) is dissolved in
saturated methanolic HCl (100 ml) and refluxed for 24 hours. The solvent,
methanol, is re-moved under reduced pressure and the residue is dissolved
in ice cold water. The aqueous solution is neutralized with 0.1N NaOH and
the solid which separates is filtered; washed well with water and air
dried to yield 10 g of product as a solid: mass spectrum 231 (M.sup.+) .
Reference Example 192
6-›(2-Methylbenzeneacetyl)amino!pyridine-3-carboxylic acid
To a cooled (0.degree. C.) mixture of 5.0 g methyl
6-aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropylethylamine in 40
ml of dichloromethane is added a solution of 12.2 g of
2-methylbenzeneacetyl chloride in 10 ml of dichloromethane. The mixture is
stirred under argon at room temperature overnight. The mixture is diluted
with 200 ml of dichloromethane and 50 ml of water and the organic layer
separated. The organic layer is washed with 50 ml each of 1M NaHCO.sub.3,
brine and dried (Na.sub.2 SO.sub.4). The solution is filtered through a
thin pad of hydrous magnesium silicate and the filtrate concentrated to
dryness. The residue (9.0 g) is chromatographed on a silica gel column
with hexane-ethyl acetate (3:1) as eluent to give 8.6 g of solid. This
solid, mainly methyl
6-››bis(2-methylbenzeneacetyl)!-amino!pyridine-3-carboxylate, is dissolved
in 60 ml of tetrahydrofuran-methanol (1:1) and 23 ml of 5N NaOH added to
the solution. The mixture is stirred at room temperature overnight and the
mixture concentrated under vacuum. Water (25 ml) is added and the mixture
is stirred and acidified with cold 1N HCl. The mixture is chilled and the
solid filtered and washed with water to give 5.9 g of off-white solid.
Reference Example 193
6-›(2-Methylbenzeneacetyl)amino!pyridine-3-carbonyl chloride
A mixture of 4.5 g of
6-›(2-methylbenzene-acetyl)amino!pyridine-3-carboxylic acid and 25 ml of
thionyl chloride is refluxed for 1 hour and then concentrated to dryness
under vacuum. To the residue is added 20 ml of toluene and the solvent
removed under vacuum. The addition and removal of toluene is repeated and
the residual solid dried at room temperature under vacuum to give 5.3 g of
dark brown solid.
Reference Example 194
2-(2-Pyridinyl)benzoic acid
A mixture of methyl 2-iodobenzoate (12 g, 47 mmol), 2-pyridinyl-tri-n-butyl
stannane (20 g, 55 mmol) and tetrakis (triphenyl phosphine) palladium (O)
(2 g), is refluxed in toluene (degassed) for 48 hours. The reaction
mixture is concentrated under vacuum and the residue is chromatographed on
a column of silica gel with 50% ethylacetate:hexane as eluent. The initial
fractions (2 lits) are discarded and finally the product methyl
2-(2-pyridinyl)benzoate, is eluted and isolated as an oil. (Yield: 5.5 g):
mass spectrum, 213 (M.sup.+)
A mixture of the preceding compound (3.0 g, 14 mmol) and NaOH (600 mg, 15
mmol) is refluxed in MeOH:water (9:1) (50 ml) for 4 hours. When the
reaction is complete, it is concentrated under vacuum and the residue
dissolved in 50 ml of cold water. Neutralization with glacial acetic acid
affords a solid which is filtered off and washed with water to give 2.5 g
of brown solid; slightly soluble in water; mass spectrum (CI) 200 (M.sup.+
1).
Reference Example 195
Ethyl
3-›N-(3-ethoxylcarbonyl-2-pyridinyl)-N-(4-methylphenylsulfonyl)!aminobutan
e-1-carboxylate
A mixture of 13.4 g of ethyl
2-›(4-methyl-phenylsulfonyl)amino!pyridine-3-carboxylate, 23.1 g of
anhydrous potassium carbonate and 20.4 g of ethyl
3-bromobutane-1-carboxylate in 300 ml of N,N-dimethylformamide is heated
at 110.degree. C. under argon for 6 hours. The mixture is concentrated to
dryness under high vacuum and to the residue is added CH.sub.2 Cl.sub.2
and H.sub.2 O. The organic layer is separated and washed with water (3
times), treated with activated carbon and dried (MgSO.sub.4). The solvent
is removed and the residue chromatographed on a short column of silica
gel. The column is eluted with 1900 ml of CH.sub.2 Cl.sub.2, then 1300 ml
of CH.sub.2 Cl.sub.2 and finally with 4 L of 5% ethyl acetate in CH.sub.2
Cl.sub.2. The 5% ethyl acetate in CH.sub.2 Cl.sub.2 fractions are combined
and the combined fraction dried (MgSO.sub.4) and the solvent removed to
give 16.9 g of white crystals. A 0.5 g sample is recrystallized from
toluene to give white crystals (washed with hexane) (0.39 g) m.p.
129.5.degree.-130.degree. C.
Reference Example 196
Ethyl
8,9-dihydro-5-hydroxy-9-›(4-methylphenyl!sulfonyl!-7H-pyrido›2,3-b›azepine
-6-carboxylic acid
To a solution of 7.85 g (70.0 mmol) of potassium tert-butoxide in 150 ml of
tetrahydrofuran, chilled in an ice bath, is added 15.2 g (35.0 mmol) of
ethyl
3-›N-(3-carbethoxy-2-pyridinyl)-N-(4-methyl-phenylsulfonyl)!aminobutane-1-
carboxylate in 150 ml of dry tetrahydrofuran dropwise over 50 min. The
mixture is stirred in an ice bath for 5 hours and poured in 500 ml of ice
water. The mixture is brought to pH 5 with 10% HCl and extracted with
ethyl acetate (4 times). The extract is dried (MgSO.sub.4) and the solvent
removed under vacuum. The residue is chromatographed on silica gel with
10% ethyl acetate in CH.sub.2 Cl.sub.2 as eluent. Fractions containing
product are combined and the solvent removed to give 12.8 g of a pale
yellow gum; Mass Spectrum (FAB) 389 (M+H); 411 (M+Na).
Reference Example 197
6,7,8,9-Tetrahydro-9-›(4-methylphenyl)sulfonyl!-5H-pyrido
›2.3-b!azepin-5-one
A mixture of 13.2 g of ethyl
8,9-dihydro-5-hydroxy-9-›(4-methylphenylsulfonyl!-7H-pyrido›2,3-b!-azepin-
6-carboxylate, 265 ml of dimethylsulfoxide and 1.52 ml of water under argon
is heated at 150.degree. C. 16.5 hours. The mixture is poured into 2700 ml
of ice water and the mixture chilled 16 hours. The mixture is filtered and
the solid washed with water and dried. The tan solid is dissolved in ethyl
acetate and the solution washed with 50 ml (4 times) of water. Activated
carbon is added to the solution and the mixture filtered through magnesium
sulfate. The filtrate is concentrated to dryness under vacuum to give 10.4
g of solid. The solid (9.24 g) is filtered through silica gel with 5%
ethyl acetate in dichloromethane as solvent. The filtrate is concentrated
under vacuum to give 6.7 g of off-white solid; Mass Spectrum (CI) (M.sup.+
+H) 317.
Reference Example 198
6,7,8,9-Tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido›3.2-b!azepine,
1-oxide
To a solution of 0.497 g of
6,7,8,9-tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido›3,2-b!azenpine in
7 ml of chloroform is added 1.04 g of 3-chloroperbenzoic acid. The mixture
is refluxed overnight and the solvent removed under vacuum. To the residue
is added 100 ml of water and the mixture extracted with dichloromethane.
The extract is washed with H.sub.2 O, 1N NaHCO.sub.3, H.sub.2 O and dried
(Na.sub.2 SO.sub.4). The solution is filtered through a thin pad of
hydrous magnesium silicate. The filter pad is washed with 10% methanol in
ethyl acetate to give 0.49 g of product as a glass (foam), m.p.
110.degree.-125.degree. C.
Reference Example 199
6,7,8,9-Tetrahydro-5H-pyrido›2,3-b!azepin-5-one
A solution of 5.00 g of
6,7,8,9-tetrahydro-9-›(4-methylphenyl)sulfonyl!-5H-pyrido›2,3-b!azepin-5-o
ne in 60 ml of 40% (v/v) sulfuric acid in acetic acid is heated at
60.degree. C. for 11 hours. The mixture is chilled and poured into 350 ml
of ice water (cooled in an ice bath) with thorough stirring. To the cold
mixture is added solid NaOH until the pH is 8 while keeping the
temperature below 30.degree. C. The mixture is filtered and the solid
washed with ethyl acetate. The organic layer of the filtrate is separated
and the aqueous layer extracted with ethyl acetate. The organic layer and
extracts are combined and treated with activated carbon. The mixture is
filtered through MGSO.sub.4 and the solvent removed under vacuum to Give
2.0 g of yellow crystals.
Reference Example 200
6,7,8,9-Tetrahydro-9-(2-chloro-4-nitrobenzyl)-5H-pyrido›2,3-b!azepin-5-one
To a solution of 6,7,8,9-tetrahydro-5Hpyrido›2,3-b!azepin-5-one and 0.234 g
of triethylamine in 6 ml of dichloromethane is added 0.506 g of
2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture
is stirred at room temperature overnight under argon. The solution is
washed with H.sub.2 O, 10% NaHCO.sub.3 and dried (MgSO.sub.4). The solvent
is removed to give a brown oil which crystallizes. The mixture is
chromatographed on silica with a waters Prep-500 instrument with ethyl
acetate-hexane (1:1) as solvent to Give 2.4 g of off-white crystals, m.p.
162.degree.-164 C. (identified as O-2-chloro-4-nitrobenzoyl derivative
(2-chloro-4-nitro-benzoyl enolate of product) and 0.80 g of product as
crystals, m.p. slowly decomposes 160.degree.-220.degree. C.
Reference Example 201
6-(4-Aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!-thieno›3,2-b!azepine
A mixture of 2.0 g of
6-(4-nitrobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!azepine
in 40 ml of absolute ethanol is stirred under argon while 1.6 ml of
hydrazine is added. The reaction mixture is heated at 60.degree. C. for
1.5 hours. The reaction mixture is cooled to room temperature and 400 mg
of 10% Pd/C added and the reaction mixture heated at 100.degree. C. for
1.5 hours. The reaction mixture is filtered through diatomaceous earth and
the cake washed with methylene chloride. The filtrate is concentrated in
vacuo to a residue which is crystallized from ethyl acetate:hexane to give
1.4 g of the desired product as yellow crystals, 242.degree.-260.degree.
C.
Reference Example 202
7-›(Dimethylamino)methylene!-4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)
-8H-thieno›3,2-b!azepin-8-one
A mixture of 3.0 g of
4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)-8H-thieno›3,2-b!azepin-8-on
e and 20 ml of tert-butoxy-bis(dimethylamino)methane is heated on a steam
bath 2 hours followed by the addition of 10 ml of methylene chloride. The
reaction mixture is refluxed for 1 hour. The reaction mixture is
evaporated in vacuo to a residue which is diluted with 100 ml of methylene
chloride and filtered through a pad of hydrous magnesium silicate. The
filtrate is filtered through a short column of silica gel to give 2.45 g
of the desired product as a yellow foam.
Reference Example 203
6-(2-Chloro-4-nitrobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!a
zepine
To a mixture of 2.2 g of
7-›(dimethyl-amino)methylene!-4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoy
l)-8H-thieno›3,2-b!azepine in 40 ml of ethanol is added 341 .mu.l of
hydrazine followed by heating at 60.degree. C. for 1.5 hours. The
volatiles are evaporated in vacuo to a residue which is dissolved in 100
ml of ethyl acetate and filtered through a pad of hydrous magnesium
silicate. The filtrate is evaporated in vacuo to give 1.85 g of the
desired product as a yellow-orange solid.
Reference Example 204
6-(2-Chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3.2-b!a
zepine
A mixture of 1.8 g of
6-(2-chloro-4-nitro-benzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b
!-azepine in 35 ml of absolute ethanol is added 5.42 g of tin (II) chloride
followed by heating at reflux for 1 hour at 80.degree. C. The volatiles
are evaporated in vacuo to a residue which is partitioned between 150 ml
of ethyl acetate and saturated aqueous NaHC.sub.3 the reactants are
stirred at room temperature for 1 hour and filtered. The organic layer is
separated and washed with 30 ml of brine, dried (Na.sub.2 SO.sub.4) and
filtered through a pad of hydrous magnesium silicate. The filtrate is
evaporated in vacuo to give 1.55 g of a yellow-orange foam.
Reference Example 205
7-›(Dimethylamino)methylene!-4,5,6,7-tetrahydro-4-4-nitrobenzyl-8H-thieno›3
,2-b!azepin-8-one
A mixture of 3.2 g of
4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno›3,2-b!azepin-8-one and 32
ml of tert-butoxybis(dimethylamino)methane is heated on a steam bath for
3.5 hours. The reaction mixture is allowed to stand for 48 hours. The
reaction mixture is evaporated in vacuo and the concentrate is dissolved
in 150 ml of methylene chloride and filtered through hydrous magnesium
silicate two times. The volatiles are evaporated in vacuo to a residue
which is dissolved in 25 ml of ethyl acetate and filtered. The filtrate is
cooled to give 3.2 g of the desired product as a light orange solid, m.p.
214.degree.-216.degree. C.
Reference Example 206
N-›4-››7-(Dimethylaminomethylene)!-5,6,7,8-tetrahydro-8-oxo-4H-thieno›3,2-b
!azepin-4-yl)carbonyl!phenyl!-2-methylbenzamide
A mixture of 100 mg of
N-›4-›(5,6,7,8-tetrahydo-8-oxo-4H-thieno›3,2-b!azepin-4-yl)carbonyl!-pheny
l!-2-methylbenzamide and 1 ml of tert-butoxybis(dimethylamino)methane is
heated at 50.degree. C. for 1 hour. To the reaction mixture is added 3 ml
of methylene chloride and heating continued for an additional 2 hours at
60.degree.-70.degree. C. The volatiles are evaporated to a residue is
dissolved in 25 ml of methylene chloride and filtered through a pad of
hydrous magnesium silicate. The filtrate is evaporated in vacuo to a
residue which is purified by chromatography on preparative thick layer
silica gel plates by elution with ethyl acetate to afford 20 mg of the
desired product as a light yellow solid.
Reference Example 207
2-Chloro-7-›(dimethylamino)methylene!-4,5,6,7-tetrahydro-4-(4-nitrobenzoyl-
8H-thieno›3,2-b!azepin-8-one
A mixture of 1.1 g of
2-chloro-4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno›3,2-b!azepin-8-on
e and 11 ml of tertbutoxy-bis(dimethylamino)methane is heated at reflux for
3.5 hours. The reaction mixture is allowed to stand for 24 hours. The
reaction mixture is evaporated in vacuo and the concentrate is purified by
column chromatography on silica gel to give 520 mg of the desired product
as a non-crystalline solid.
Reference Example 208
8-Chloro-2,4,5,6-tetrahydro-2-methyl-6-(4-nitrobenzyl)pyrazolo›3,4-d!thieno
›3,2-b!azepine
A mixture of 500 mg of
2-chloro-7-›(dimethylamino)methylene!-4,5,6,7-tetrahydro-4-(4-nitrobenzoyl
)-8H-thieno›3,2-b!azepin-8-one in 15 ml of absolute methanol is stirred
under argon while 131 .mu.l of N-methylhydrazine is added. The reaction
mixture is heated at 80.degree. C. for 18 hours. The reaction mixture is
cooled to room temperature and concentrated in vacuo to give 420 mg of the
desired product as a solid.
Reference Example 209
6-(2-Chloro-4-aminobenzoyl)!-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!
azepine
As described for Reference Example 204,
6-(2-chloro-4-nitrobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!
azepine is reduced with stannus chloride (SnCl.sub.2) in ethanol to give
the product as a solid.
Reference Example 210
5-(2-Chloro-4-aminobenzoyl)-4,10-dihydro-5H-pyrido›3,2-b!thieno›2,3-e!azepi
ne
As described for Reference Example 204
5-(2-chloro-4-nitrobenzoyl)-4,10-dihydro-5H-pyrido›3,2-b!-thieno›2,3-e!aze
pine is reduced with stannus chloride (SnCl.sub.2) in ethanol to give the
product as a solid.
Reference Example 211
5-(2-Chloro-4-aminobenzoyl)-6,10-dihydro-5H-pyrido›3,2-b!thieno›3,2-e!azepi
ne
As described for Reference Example 204
5-(2-chloro-4-nitrobenzoyl)-6,10-dihydro-5H-pyrido›3,2-b!-thieno›3,2-e!aze
pine is reduced with stannus chloride (SnCl.sub.2) in ethanol to give the
product as a solid.
Reference Example 212
5-(4-Nitrobenzyl)-6,7,8,9-tetrahydro-5H-pyrido-›3,2-b!azepine
A solution of 2.96 g of 6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine, 3.03 g
of triethylamine and 4.45 g of 4-nitrobenzoyl chloride in 30 ml of
dichloromethane is stirred under argon at room temperature for 4 hours.
The mixture is poured into water and the organic layer separated and
washed with saturated NaHCO.sub.3, H.sub.2 O and brine. The organic layer
is dried (Na.sub.2 SO.sub.4) and filtered through a thin pad of hydrous
magnesium silicate. The filtrate is concentrated to dryness to give 6.35 g
of solid. Trituration with 25 ml of dichloromethane gives 5.50 g of light
yellow solid. A sample from a prior run in trituration gives white
crystals, m.p. 231.degree.-233.degree. C.
Reference Example 213
5-(4-Nitrobenzoyl)-6,7,8,9-tetrahydro-5-H-pyrido›3,2,-b!-azepine, 1-oxide
A mixture of 1.18 g of
5-(4-nitrobenzoyl)-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine and 1.37 g
of 3-chloroperoxybenzoic acid in 10 ml of dichloromethane is stirred at
room temperature overnight under argon. The mixture is diluted with 15 ml
of dichloromethane and the solution washed with 1N NaHCO.sub.3, H.sub.2 O,
brine and dried (Na.sub.2 SO.sub.4). The solution is filtered through a
thin pad of hydrous magnesium silicate. The filter pad is washed with 50
ml of ethyl acetate. Then the filter pad is washed with ethyl
acetate-methanol (5:1) and the ethyl acetate-methanol wash collected and
the solvent removed to give 0.86 g of crystals, m.p.
231.degree.-233.degree. C.
Reference Example 214
5-(2-Chloro-4-nitrobenzoyl)-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine,
1-oxide
A mixture of 0.497 g of
5-(2-chloro-4-nitro-benzoyl)-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine
and 0.38 g of 3-chloroperoxybenzoic acid in 7 ml of dichloromethane is
refluxed under argon for 16 hours. The solvent is removed under argon and
to the residue is added water. The mixture is extracted with
dichloromethane and the extract washed with 1N NaHCO.sub.3, H.sub.2 O and
dried (Na.sub.2 SO.sub.4). The solution is filtered through a thin pad of
hydrous magnesium silicate. The pad is washed with ethyl acetate and then
with ethyl acetate-methanol (9:1). The ethyl acetate-methanol wash is
collected separately and the solvent removed under vacuum to give the
product as a glass, m.p. 110.degree.-125.degree. C.
Reference Example 215
5-(2-Chloro-4-nitrobenzyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!aze
pine, O-acetate
A mixture of 0.49 g of
5-(2-chloro-4-nitrobenzoyl)-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine,
1-oxide in 5 ml of acetic anhydride is heated in an oil bath at 90.degree.
for 36 hours. Toluene (25 ml) is added and the mixture concentrated under
high vacuum. The process is repeated and the residue chromatographed on
silica gel preparative plates with ethyl acetate as solvent to give 0.24 g
of crystals, m.p. 162.degree.-165.degree. C. Anal. Calc'd for C.sub.18
H.sub.15 ClN.sub.3 O.sub.5. C, 55.5;H, 4.1;N, 10.8. Found: C, 55.5; H,
4.0; N, 10.6.
Reference Example 216
5-(4-Nitrobenzyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine,
O-acetate
A mixture of 0.58 g of
5-(4-nitrobenzoyl)-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine, 1-oxide and
5 ml of acetic anhydride in 10 ml of dichloromethane is refluxed for 2
days. An additional 2 ml of acetic anhydride is added and the mixture
refluxed 2 days. To the mixture is added toluene (30 ml-twice) and the
solvent removed under high vacuum. The residue is chromatographed on
silica gel preparative plates with ethyl acetate as solvent to give 0.37 g
of crystals, m.p. 135.degree.-137.degree. C.
Reference Example 217
5-(4-Nitrobenzyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine
To a mixture of 0.5 g of
5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine,
O-acetate in 10 ml of methanol-water (8:2) is added KHCO.sub.3 and the
mixture stirred at room temperature overnight. The mixture is concentrated
under vacuum, diluted with 10 ml of water and extracted with ethyl
acetate. The extract is dried (Na.sub.2 SO.sub.4) and the solvent removed
to give the product as a solid. Chromatography on silica gel with ethyl
acetate as solvent gives crystals, m.p. 182.degree.-185.degree. C.
Reference Example 218
5,6,7,8-Tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido›3.2-b!azepin-9-one
A mixture of 0.5 g of
5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine in
5 ml of dimethyl sulfoxide and 1 ml of acetic anhydride is stirred at room
temperature 16 hours. To the mixture is added 10 ml of water and 1N
NaHCO.sub.3. The mixture is extracted with ethyl acetate and the extract
washed with water, 1N NaHC.sub.3, brine and dried. The solvent is removed
to give a solid. chromatography on silica gel with ethyl acetate as
solvent gives the product as a solid, m.p. 188.degree.-190.degree. C.
Reference Example 219
5,6,7,8-Tetrahydro-5-(2-chloro-4-nitrobenzyl)-9H-pyrido›3,2-b!azepin-9-one
As described for Reference Example 218,
5-(2-chloro-4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!a
zepine is reacted with dimethylsulfoxideacetic anhydride to give the
product as a solid.
Reference Example 220
6,7,8,9-Tetrahydro-9-(4-nitrobenzyl)-5H-pyrido›2,3-b!azepin-5-one
To a solution of 2.11 g of 6,7,8,9-tetrahydro-5H-pyrido›2,3-d!azepin-5-one
in 40 ml of dichloromethane is added 3.28 g of solid NaHCO.sub.3. To the
stirred mixture under argon is added dropwise 3.14 g of 4-nitrobenzoyl
chloride in 30 ml of dichloromethane containing 2 ml of tetrahydrofuran
and the mixture is stirred overnight. To the mixture is added
tetrahydrofuran and water and the mixture filtered. The solid is washed
with chloroform (solid dissolved) and the organic layer of the filtrate
separated. The organic layer is filtered through MgSO.sub.4 and the
filtrate concentrated to dryness to give a white solid. The solid from two
runs is dissolved in ethyl acetate--CH.sub.2 Cl.sub.2 (2:8) and filtered
through short silica gel column and the product fraction collected. The
solvent is removed and the solid disolved in hot chloroform-methanol and
the solution treated with activated carbon. The mixture is filtered
through diatomaceous earth and the filtrate concentrated to dryness under
vacuum to give 7.73 g of white crystals; Mass Spectrum (CI) (CH.sub.4):
312 (MH.sup.+).
Reference Example 221
6-›(Dimethylamino)methylene!-6,7,8,9-tetrahydro-9-(4-nitrobenzyl)-5H-pyrido
›2,3-b!azepin-5-one
To a slurry of 0.50 g of
6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido›2,3-b!azepin-5-one in 10
ml of tetrahydrofuran under argon is added 0.70 g of
tert-butoxy-bis(dimethylamino)methane and the mixture is stirred at room
temperature overnight. The volatiles are removed under vacuum and the
residue in ethyl acetate--CH.sub.2 Cl.sub.2 (2:8) filtered through a short
column of silica gel. The silica gel is washed with ethyl acetate
(discard) and then with chloroform containing 3% methanol to give 0.51 g
of the product as a yellow solid.
Reference Example 222
6-›(Dimethylamino)methylene!-6,7,8,9-tetrahydro-9-(2-chloro-4-nitrobenzyl)-
5H-pyrido›2,3-b!azepin-5-one
To a solution of 0.20 g of
6,7,8,9-tetrahydro-9-(2-chloro-4-nitrobenzoyl)-5H-pyrido›2,3-b!azepin-5-on
e in 2 ml of dioxane is added 0.504 g of
tert-butoxybis-(dimethylamino)methane and the mixture is stirred at room
temperature. The volatiles are removed under high vacuum. The residue is
dissolved in ethyl acetate --CH.sub.2 Cl.sub.2 (3:7) and the solution
passed through a short column of silica gel (ethyl acetate --CH.sub.2
Cl.sub.2) eluate is discarded). Elution with ethyl acetate --CH.sub.2
Cl.sub.2 (8:2) gives the product as a yellow glass (0.19 g); Mass Spectrum
(CI) (CH.sub.4); 401 (MH.sup.+).
Reference Example 223
1,4,5,6-Tetrahydro-6(4-nitrobenzoyl)pyrazolo›3,4d!pyrido›2,3-b!azepine
To a slurry of 0.51 g of
6-›(dimethylamino)-methylene!-6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyr
ido›2,3-b!azepin-5-one in 17 ml of methanol under argon is added 0.14 g of
hydrazine hydrate. The mixture is stirred overnight and the solvent
removed under vacuum. The residue is dissolved in hot chloroformmethanol
(95:5) and filtered through silica gel and washed filter pad with
chloroform-methanol (95:5). The filtrate is concentrated to dryness to
give 0.48 g of yellow solid.
Reference Example 224
1,4,5,6-Tetrahydro-6-(4-aminobenzoyl)pyrazolo ›3,4d!pyrido›2,3-b!azepine
To a slurry of 0.170 g of
1,4,5,6-tetrahydro-6-(4-nitrobenzoyl)pyrazolo›3,4-d!pyrido›2,3-b!azepine
in 8 ml of ethanol under argon is added 0.573 g of stannous chloride
dihydrate (SnCl.sub.2.2H.sub.2 O). The mixture is refluxed for 1 hour,
diluted with ice-water and made basic with 10% NaHCO.sub.3 solution. The
mixture is stirred 3.5 hours and extracted with chloroform (3 times). The
extract is dried (MgSO.sub.4) and the solvent removed under vacuum.
Chromatography on silica gel with ethyl acetate as eluent gives 0.10 g of
off-white crystals.
Reference Example 225
8›(Dimethylamino)methylene!-5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido
›3,2-b!azepin-9-one
As described for Reference Example 221,
5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido›3,2-b!azepin -9-one is
reacted with tert-butoxybis(dimethylamino)methane to give the product as a
solid.
Reference Example 226
1,4,5,6-Tetrahydro-6-(4,5-nitrobenzyl)pyrazolo›3,4-d!pyrido›3,2-b!azepine
As described for Reference Example 223,
8-›(dimethylamino)methylene!-5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyri
do›3,2-b!azepin-9-one is reacted with hydrazine hydrate to give the product
as a solid, m.p. 255.degree.-256.degree. C.
Reference Example 227
5,6-Dihydro-6-(4H-isoxazolo›5,4-d!-thieno›3,2-b!azepin
A mixture of 0.50 g of
7-›(dimethylamino)methylene!4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thien
o›3,2-b!azepin-8-one, 0.234 g of hydroxylamine, hydrochloride and 16 ml of
methanol is refluxed for 4 hours. The mixture is chilled and filtered and
the solid washed with a small amount of cold methanol and cold ethyl
acetate to give 0.41 g of tan crystals, m.p. 218.degree.-222.degree. C.
The preceding compound in ethanol is refluxed with SnCl.sub.2.H.sub.2 O
for one hour, cooled and diluted with ice-water. The mixture is made basic
with 10% NaHCO.sub.3 and is stirred for 3.5 hours at room temperature. The
mixture is extracted with ethyl acetate and the extract washed with brine.
The extract is dried (Na.sub.2 SO.sub.4) and the solvent removed. The
residue is chromatographed on silica gel with ethyl acetate-hexane as
solvent to give the product as a solid.
Reference Example 228
5,6,7,8-Tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido›3,2-b!azepin-9-one
A mixture of 0.313 g of
5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido›3,2-b!azepine, 4
ml of CH.sub.2 Cl.sub.2 and 0.75 ml of dimethylsulfoxide is chilled to
-25.degree. C. and 0.405 g of cyanuric chloride is added. The mixture is
allowed to stand at -25.degree. C. for 6.5 hours and 0.41 g of
triethylamine is added. The mixture is stirred 10 minutes and poured into
water. The mixture is extracted with dichloromethane and the extract
washed with water, brine and dried (Na.sub.2 SO.sub.4). The solvent is
removed to give 0.39 g of solid. Chromatography on silica gel with ethyl
acetate as solvent gives 0.17 g of crystals, m.p. 188.degree.-190.degree.
C.
Reference Example 229
Methyl 4-›(›1,1'-Biphenyl!-2-carbonyl)amino!-3-methoxybenzoate
A mixture of 10.0 g of ›1,1'-biphenyl!-2-carboxylic acid in 75 ml of
methylene chloride and 12.52 g of oxalyl chloride is stirred at room
temperature for 15 hours. The volatiles are evaporated in vacuo to give
11.06 g of an oil. A 2.16 g portion of the above oil in 25 ml of methylene
chloride is reacted with 1.81 g of methyl 4-amino-3-methoxybenzoate and
1.30 g of N,N-diisopropylethylamine by stirring at room temperature for 18
hours. The reaction mixture is washed with water, saturated aqueous
NaHCO.sub.3 and the organic layer dried(Na.sub.2 SO.sub.4). The organic
layer is passed through hydrous magnesium silicate and hexane added to the
filtrate at the boil to give 3.20 g of the desired product as a
crystalline solid, m.p. 115.degree.-117.degree. C.
Reference Example 230
Methyl 4-›(›1,1'-Biphenyl!-2-carbonyl)amino!-2-chlorobenzoate
A solution of 2.37 g of ›1,1'-biphenyl!-2-carbonyl chloride in 10 ml of
methylene chloride is added dropwise to an ice cold solution of 1.84 g of
methyl 4-amino-2-chlorobenzoate and 1.49 g of N,N-diisopropylethylamine in
50 ml of methylene chloride. The reaction mixture is stirred at room
temperature for 18 hours and washed with water, saturated aqueous
NaHCO.sub.3 and the organic layer dried(Na.sub.2 SO.sub.4). The organic
layer is passed through a pad of hydrous magnesium silicate and hexane
added at the boil to give 1.1 g of the desired product as a crystalline
solid, m.p. 132.degree.-134.degree. C. M.sup.+ H=365
Reference Example 231
4-›(›1,1'-Biphenyl!-2-carbonyl)amino!-2-chlorobenzoic Acid
A mixture of 3.0 g of methyl
4-›(›1,1'-biphenyl!-2-carbonyl)amino!-2-chlorobenzoate in 75 ml of
absolute ethanol and 2.0 ml of 10N sodium hydroxide is heated on a steam
bath for 3 hours. Water is added to obtain a solution which is extracted
with methylene chloride. The aqueous phase is acidified with acetic acid
and the resulting solid collected and dried in vacuo at 80.degree. C. to
give 0.1 g of the desired product as a crystalline solid, m.p.
217.degree.-219.degree. C.
Reference Example 232
4-›(›1,1'-Biphenyl!-2-carbonyl)-amino!-3-methoxybenzoyl Chloride
A solution of 2.69 g of 4-›(›1,1'-biphenyl!-2-carbonyl!amino!-3-methoxy
benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1
hour under Argon. The volatiles are removed in vacuo to give a residue
which is stirred with hexane to give 2.58 g of crystalline solid, m.p.
121.degree.-123.degree. C. M.sup.+ =361.
Reference Example 233
Methyl 4-›(›1,1'-Biphenyl!-2-carbonyl)amino!benzoate
A mixture of 10.0 g of ›1,1'-biphenyl!-2-carboxylic acid in 75 ml of
methylene chloride and 12.52 g of oxalyl chloride is stirred at room
temperature for 18 hours. The volatiles are evaporated in vacuo to give
11.66 g of an oil. A 7.5 g portion of the above oil in 25 ml of methylene
chloride is added dropwise to a solution of 4.53 g of
methyl-4-aminobenzoate and 4.3 g of N,N-diisopropylethylamine in 100 ml of
methylene chloride at 0.degree. C. The reaction mixture is stirred at room
temperature for 18 hours and washed with water, and saturated aqueous
NaHCO.sub.3 and the organic layer dried(Na.sub.2 SO.sub.4). The organic
layer is passed through hydrous magnesium silicate and hexane added to the
filtrate at the boil to give 8.38 g of the desired product as a
crystalline solid, m.p. 163.degree.-165.degree. C.
Reference Example 234
4-›(›1,1'-Biphenyl!-2-carbonyl)amino!benzoic Acid
A 3.15 g sample of methyl 4-›(›1,1'-biphenyl!-2-carbonyl)amino!benzoate is
refluxed for 8 hours in 100 ml of ethyl alcohol and 2.5 ml of 10N sodium
hydroxide. The cooled reaction mixture is acidified with››? acid!!and the
desired product collected and dried to give 2.9 g of the desired product
as a solid m.p. 246.degree.-249.degree. C. M+H=318.
Reference Example 235
4-›(›1,1'-Biphenyl!-2-carbonyl)amino!benzoyl Chloride
A mixture of 1.39 g of 4-›(›1,1'-biphenyl!-2-carbonyl)amino!benzoic acid in
2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. Cold
hexane is added and the crystalline solid collected and dried to give 1.34
g of the desired product, m.p. 118.degree.-120.degree. C.
Reference Example 236
2-(Phenylmethyl)benzoyl Chloride
A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl
chloride is heated on a steam bath for 1 hour. The volatiles are
evaporated in vacuo to give 5.74 g of the desired product as an oil.
M.sup.+ =227 as methyl ester.
Reference Example 237
Methyl 4-››2-(Phenylmethyl)benzoyl!amino!benzoate
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine
in 75 ml of methylene chloride is added 5.54 g of 2-(phenylmethyl)benzoyl
chloride and the reactants stirred at room temperature for 18 hours. The
reaction mixture is washed with water, saturated aqueous NaHCO.sub.3 and
the organic layer dried(Na.sub.2 SO.sub.4). The organic layer is passed
through hydrous magnesium silicate two times and hexane added to the
filtrate at the boil to give 5.04 g of the desired product as a
crystalline solid, m.p. 138.degree.-139.degree. C.
Reference Example 238
Sodium 4-››2-(phenylmethyl)benzoyl!amino!benzoate
A mixture of 4.90 g of methyl 4-››2-(phenyl-methyl)benzoyl!amino!benzoate
in 100 ml of absolute ethanol and 3.50 ml of 10N sodium hydroxide is
heated on a steam bath for 3 hours. The aqueous phase is filtered and the
resulting solid collected and dried to give 4.25 g of the desired product
m.p. 340.degree.-346.degree. C.
Reference Example 239
4-››2-(Phenylmethyl!benzoyl!amino!benzoic Acid
A mixture of 4.0 g sodium 4-››2-(phenylmethyl)benzoyl!amino!benzoate is
suspended in water and the pH adjusted to 5 with acetic acid. The solid is
collected by filtration and dried at 80.degree. C. in vacuo to give 3.75 g
of the desired product, 246.degree.-247.degree. C. M.sup.+ =332.
Reference Example 240
4-››2-(Phenylmethyl)benzoyl!amino!benzoyl Chloride
A mixture of 2.0 g of 4-››2-(phenylmethyl)benzoyl!amino!benzoic acid in 2.0
ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles
are evaporated in vacuo to give 1.53 g of the desired product as an oil.
M.sup.+ =346 as methyl ester.
Reference Example 241
Methyl 4-››(2-Phenylmethyl)benzoyl!amino!-2-chlorobenzoate
A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl
chloride is heated on a steam bath for 1 hour. The volatiles are
evaporated in vacuo to give 5.70 g of an oil. A 2.85 g portion of the
above oil in 25 ml of methylene chloride is added to a solution of 50 ml
of methylene chloride containing 1.85 g of methyl 4-amino-2-chlorobenzoate
and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature
for 18 hours. The reaction mixture is washed with water, saturated aqueous
NaHCO.sub.3 and the organic layer dried(Na.sub.2 SO.sub.4). The organic
layer is passed through hydrous magnesium silicate two times and hexane
added to the filtrate at the boil to give 2.96 g of the desired product as
a crystalline solid, m.p. 133.degree.-135.degree. C. M.sup.+ =380.
Reference Example 242
Methyl 4-››(2-phenylmethyl)benzoyl!amino!-3-methoxybenzoate
A solution of 2.85 g of 2-(phenylmethyl)benzoyl chloride in 25 ml of
methylene chloride is added dropwise to an ice cold solution of 1.84 g of
methyl 4-amino-3-methoxybenzoate and 1.61 g of N,N-diisopropylethylamine
in 50 ml of methylene chloride. The reaction mixture is stirred at room
temperature for 18 hours and washed with water, saturated aqueous
NaHCO.sub.3 and the organic layer dried(Na.sub.2 SO.sub.4). The organic
layer is passed through a pad of hydrous magnesium silicate and hexane
added at the boil to give 2.2 g of the desired product as a crystalline
solid, m.p. 129.degree.-131.degree. C. M.sup.+ =376.
Reference Example 243
2-Chloro-4-››(2-Phenylmethyl)benzoyl!amino!benzoic Acid
A mixture of 2.8 g of methyl
2-chloro-4-››(2-phenylmethyl)benzoyl!aminobenzoate in 75 ml of absolute
ethanol and 1.84 ml of 10N sodium hydroxide is heated on a steam bath for
3 hours. Water is added to obtain a solution which is extracted with
methylene chloride. The aqueous phase is acidified with acetic acid and
the resulting solid collected and dried in vacuo at 80.degree. C. to give
2.6 g of the desired product as a crystalline solid, m.p.
184.degree.-187.degree. C. M.sup.+ H=366.
Reference Example 244
3-Methoxy-4-››(2-phenylmethyl)benzoyl!amino!benzoate
A mixture of 2.05 g of methyl
4-››(2-phenylmethyl)benzoyl!amino!-3-methoxybenzoate in 75 ml of absolute
ethanol and 1.4 ml of 10N sodium hydroxide is heated on a steam bath for 3
hours. Water is added to obtain a solution which is extracted with
methylene chloride. The aqueous phase is acidified with acetic acid and
the resulting solid collected and dried in vacuo at 80.degree. C. to give
1.87 g of the desired product as a crystalline solid, m.p.
176.degree.-178.degree. C. M.sup.+ H=362.
Reference Example 245
3-Methoxy-4-››(2-phenylmethyl)benzoyl!amino!benzoyl
A mixture of 1.71 g of 3-methoxy-4-››(2-phenylmethyl)benzoyl!amino!benzoic
acid in 2.0 ml of thionyl chloride is heated on a steam bath under Argon
for 1 hour and hexane added. The resulting solid is collected and dried to
give 1.71 g of the desired product as a crystalline solid, m.p.
130.degree.-135.degree. C. M.sup.+ =376 as the methyl ester.
Reference Example 246
›4'-(Trifluoromethyl)-1,1'-biphenyl!-2-carbonyl Chloride
A mixture of 5.0 g of 4'-(trifluoromethyl)›1,1'-biphenyl!-2-carboxylic acid
in 5.0 ml of thionyl chloride is heated on a steam bath under Argon for 1
hour and hexane added. The resulting solid is collected and dried to give
5.36 g of the desired product as a colorless oil. M.sup.+ =280 as methyl
ester.
Reference Example 247
Methyl
2-Chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!carbonyl)amino!benzoate
A solution of 3.13 g of ›4'-(trifluoromethyl)-›1,1'-biphenyl!-2-carbonyl
chloride in 25 ml of methylene chloride is added dropwise to an ice cold
solution of 1.84 g of methyl 4-aminobenzoate and 1.43 g of
N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction
mixture is stirred at room temperature for 18 hours and washed with water,
saturated aqueous NaHCO.sub.3 and the organic layer dried(Na.sub.2
SO.sub.4). The organic layer is passed through a pad of hydrous magnesium
silicate and hexane added at the boil to give 3.36 g of the desired
product as a crystalline solid, m.p. 164.degree.-165.degree. C. M.sup.+
=396.
Reference Example 248
3-Methoxy-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoyl
Chloride
A mixture of 2.0 g of
3-methoxy-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoi
c acid in 20 ml of thionyl chloride is heated on a steam bath under Argon
for 1 hour and hexane added. The resulting solid is collected and dried to
give 1.92 g of the desired product as a crystalline solid, m.p.
136.degree.-138.degree. C.
Reference Example 249
3-Methoxy-4-›(›4'-trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoic
Acid
A mixture of 3.78 g of methyl
3-methoxy-4-›(›4'-trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!-benzoa
te in 75 ml of absolute ethanol and 2.20 ml of 10 N sodium hydroxide is
heated on a steam bath for 3 hours. Water is added to obtain a solution
which is extracted with methylene chloride. The aqueous phase is acidified
with acetic acid and the resulting solid collected and dried in vacuo at
80.degree. C. to give 3.49 g of the desired product as a crystalline
solid, m.p. 213.degree.-215.degree. C.
Reference Example 250
Methyl
3-Methoxy-4-›(›4'-trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoat
A solution of 3.56 g of ›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl
chloride in 25 ml of methylene chloride is added dropwise to an ice cold
solution of 1.81 g of methyl 4-amino-3-methoxybenzoate and 1.62 g of
N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction
mixture is stirred at room temperature for 18 hours and washed with water,
saturated aqueous NaHCO.sub.3 and the organic layer dried(Na.sub.2
SO.sub.4). The organic layer is passed through a pad of hydrous magnesium
silicate and hexane added at the boil to give 3.9 g of the desired product
as a crystalline solid, m.p. 112.degree.-113.degree. C.
Reference Example 251
2-Chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoyl
Chloride
A mixture of 1.39 g of
2-chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoic
acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour.
The reaction mixture is concentrated to a residue in vacuo to a residue.
Cold hexane is added to the residue and the solid collected and dried to
give 1.39 g of the desired product.
Reference Example 252
2-Chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoic
acid
A mixture of 3.83 g of methyl
2-chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoat
e in 75 ml of absolute ethanol and 2.20 ml of 10N sodium hydroxide is
heated on a steam bath for 3 hours. Water is added to obtain a solution
which is extracted with methylene chloride. The aqueous phase is acidified
with acetic acid and the resulting solid collected and dried in vacuo at
80.degree. C. to give 3.42 g of the desired product as a crystalline
solid, m.p. 187.degree.-189.degree. C.
Reference Example 253
Methyl
2-chloro-4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoat
e
A solution of 3.56 g of ›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl
chloride in 10 ml of methylene chloride is added dropwise to an ice cold
solution of 1.86 G of methyl 2-chloro-4-aminobenzoate and 1.6 G of
N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction
mixture is stirred at room temperature for 18 hours and washed with water,
saturated aqueous NaHCO.sub.3 and the organic layer dried(Na.sub.2
SO.sub.4). The organic layer is passed through a pad of hydrous magnesium
silicate(3.times.) and hexane added to the filtrate at the boil to give
4.0 g of the desired product as a crystalline solid, m.p.
130.degree.-132.degree. C.
Reference Example 254
4-›(›4'-(Trifluoromethyl)›1,1'-biphenyl!carbonyl)amino!benzoic Acid
A mixture of 3.0 g of methyl
4-›(›4'-(trifluoromethyl)›1,1'-biphenyl!-2-carbonyl)amino!benzoate in 75
ml of absolute ethanol and 2.0 ml of 10N sodium hydroxide is heated on a
steam bath for 3 hours. Water is added to obtain a solution which is
extracted with methylene chloride. The aqueous phase is acidified with
acetic acid and the resulting solid collected and dried in vacuo at
80.degree. C. to give 2.93 g of the desired product as a crystalline
solid, m.p. 243.degree.-245.degree. C. M.sup.+ =385.
Reference Example 255
Methyl 6-››3-(2-Methylpyridinyl)carbonyl!amino!pyridine-3-carboxylate
To a stirred solution of 3 g of methyl 6-aminopyridine-3-carboxylate and 4
ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is added
dropwise a solution of 6.4 g of 2-methylpyridine-3-carbonyl chloride in 25
ml of methylene chloride. The reaction mixture is stirred at room
temperature for 2 hours and quenched with water. The organic layer is
washed with water, dried(MgSO.sub.4), filtered and evaporated in vacuo to
a residue which is stirred with ether and the resulting solid collected
and air dried to give 6.8 g of the desired product. M.sup.+ =390.
Reference Example 256
6-››3-(2-methylpyridinyl)carbonyl!amino!pyridine-3-carboxylic Acid
To a solution of 6.5 g of methyl
6-››3-(2-methylpyridinyl)carbonyl!amino!pyridine-3-carboxylate in 100 ml
of 1:1 tetrahydrofuran:methyl alcohol is added 20 ml of 5N NaOH. The
reaction mixture is stirred overnight and evaporated in vacuo to a
residue. The residue is dissolved in water and neutralized with acetic
acid. The separated solid is filtered and air-dried to give 3.0 g of the
desired product. M.sup.+ =257.
Reference Example 257
Methyl 6-›(›1,1'-Biphenyl!-2-carbonyl)amino!-pyridine-3-carboxylate
To a solution of 1.5 g of methyl 6-amino-pyridine-3-carboxylate in 100 ml
of methylene chloride is added 3 ml of N,N-diisopropylethylamine at room
temperature. To the stirred reaction mixture is slowly added a solution of
2.5 g of ›1,1'-biphenyl!-2-carbonyl chloride. The reaction mixture is
stirred at room temperature for 4 hours and then quenched with water. The
organic layer is washed well with water and dried over anhydrous
MgSO.sub.4, filtered and evaporated in vacuo to a solid residue. The
residue is stirred with ether, filtered and dried to give 3.0 g of the
desired product: M.sup.+ =332.
Reference Example 258
6-›(›1,1'-Biphenyl!-2-carbonyl)amino!pyridine-3-carboxylic Acid
To a stirred solution of 2.5 g of methyl
6-›(›1,1'-Biphenyl!-2-carbonyl)amino!-pyridine-3-carboxylate in 50 ml of
1:1 tetrahydrofuran:methanol is added 10 ml of 5N sodium hydroxide and the
mixture stirred at room temperature for 16 hours. The reaction mixture is
concentrated in vacuo to a residue which is dissolved in water and
neutralized with acetic acid. The separated colorless solid is filtered
and air dried to give 2.0 g of the desired product: M+=318.
EXAMPLE 1
N-›4-›(4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-2-chloro-4-fluorobenzamide
To an ice bath cooled mixture of 296 mg of
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!-thieno›3,2-b!azepine
in 3.5 ml of methylene chloride is added 417 .mu.1 of triethylamine
followed by a solution of 483 mg of 2-chloro-4-fluorobenzoyl chloride in
1.5 ml of methylene chloride. The reaction mixture is stirred at room
temperature for 18 hours under argon. An additional 40 ml of methylene
chloride is added followed by 20 ml of water. The organic layer is washed
with 20 ml each of 2N citric acid, 1M NaHCO.sub.3 and brine. The organic
layer is dried (Na.sub.2 SO.sub.4), filtered through hydrous magnesium
silicate and the filtrate evaporated in vacuo to give a residue which is
crystallized from ethyl acetate:hexane to give 520 mg of a white solid. To
a suspension of 340 mg of the preceding compound in 5 ml methanol is added
1.2 ml of 1N NaOH. The reactants are stirred at room temperature for 1
hour. The reaction mixture is evaporated in vacuo to a residue which is
diluted with 100 ml of ethyl acetate and filtered. The filtrate is washed
with 30 ml each of water, brine and dried (NaSO.sub.4). The organic layer
is passed through a pad of hydrous magnesium silicate. The filtrate is
evaporated in vacuo to a residue which is stirred with ethyl
acetate:hexane to give 255 mg of white crystalline solid, m.p.
258.degree.-266.degree. C.
EXAMPLE 2
N-›4-›(4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2methylbenzamide
To an ice bath cooled mixture of 297 mg of
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!azepine
in 3.5 ml of methylene chloride is added 417 .mu.l of triethylamine
followed by a solution of 432 mg of 2-methyl-5-fluorobenzoyl chloride in
1.5 ml of methylene chloride. The reaction mixture is stirred at room
temperature for 18 hours under argon. An additional 50 ml of methylene
chloride is added followed by 20 ml of water. The organic layer is washed
with 20 ml each of 2N citric acid, 1M NaHCO.sub.3 and brine. The organic
layer is dried (Na.sub.2 SO.sub.4), filtered through hydrous magnesium
silicate and the filtrate evaporated in vacuo to give 570 mg of a foam
residue. To a suspension of 564 mg of the preceding compound in 4 ml of
methanol and 4 ml of tetrahydrofuran is added 2.0 ml of 1N NaOH. The
reactants are stirred at room temperature for 2 hours. The reaction
mixture is diluted with 2 ml of 1N HCl and evaporated in vacuo to a
residue which is partitioned between 50 ml of ethyl acetate and 20 ml of
water. The resulting solid is collected, washed with ethyl acetate and
dried to give 305 mg of the desired product as white crystals, m.p.
310.degree.-312.degree. C.
EXAMPLE 3
N-›4-›(4,5-Dihydropyrazolo›3,4!thieno›3,2-b!azepin-6-(1H)-yl)carbonyl!-3-ch
lorophenyl!-5-fluoro-2-methylbenzamide
To an ice bath cooled mixture of 345 mg of
6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!
azepine in 3.5 ml of methylene chloride is added 417 .mu.l of triethylamine
is added a solution of 432 mg of 2-methyl-5-fluorobenzoyl chloride in 1.5
ml of methylene chloride. The reaction mixture is stirred at room
temperature for 18 hours under argon. An additional 40 ml of methylene
chloride is added followed by 20 ml of water. The organic layer is washed
with 20 ml each of 2N citric acid, 1M NaHCO.sub.3 and brine. The organic
layer is dried (Na.sub.2 SO.sub.4), filtered through hydrous magnesium
silicate and the filtrate evaporated in vacuo to give a foam residue. To a
solution of 800 mg of the preceding compound in 4 ml methanol and 4 ml of
tetrahydrofuran is added 2.7 ml of 1N NaOH. The reactants are stirred at
room temperature for 1.5 hours. The reaction mixture is neutralized with
1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of
methylene chloride and water and then filtered. The collected solid is
dried at 60.degree. C. to give 275 mg of the desired product as an
off-white solid, m.p. 310.degree.-312.degree. C.
EXAMPLE 4
N-›4-›(4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-5-chloro-2-fluorobenzamide
To an ice bath cooled mixture of 345 mg of
6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!
azepine in 3.5 ml of methylene chloride under argon is added 417 .mu.l of
triethylamine followed by a solution of 482 mg of 2-fluoro-5-chlorobenzoyl
chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred
at room temperature for 18 hours under argon. An additional 40 ml of
methylene chloride is added followed by 20 ml of water. The organic layer
is washed with 20 ml each of 2N citric acid, 1M NaHCO.sub.3 and brine. The
organic layer is dried (Na.sub.2 SO.sub.4), filtered through hydrous
magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of
the desired product as a solid residue. To a solution of 500 mg of the
preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added
1.51 ml of 1N NaOH. The reactants are stirred at room temperature for 18
hours. The reaction mixture is neutralized with 1N HCl and evaporated in
vacuo to a residue which is diluted with 50 ml of chloroform and washed
with water, brine and dried (Na.sub.2 SO.sub.4). The organic layer is
passed through a pad of hydrous magnesium silicate. The filtrate is
evaporated in vacuo to a residue which is crystallized from ethyl acetate
containing ethyl alcohol. The collected solid is dried to give 215 mg of
the desired product as an off white solid, m.p. 282.degree.-288.degree. C.
EXAMPLE 5
N-›4-››4,5-Dihydro-2-methylpyrazolo›3,4-d!thieno›3,2-b!-azepin-6-(2H)-yl!ca
rbonyl!phenyl!2,4-dichlorobenzamide
To an ice bath cooled mixture of 290 mg of
2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo›3,4-d!thieno›3,2-b!
azepine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon
is added 186 .mu.l of triethylamine followed by 156 .mu.of
2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room
temperature for 18 hours under argon. The reaction mixture is evaporated
in vacuo to a residue which is dissolved in 50 ml of methylene chloride
and washed with 20 ml each of water, 1N NaHCO.sub.3, 2N citric acid and
brine. The organic layer is dried (Na.sub.2 SO.sub.4) and filtered. The
filtrate is concentrated in vacuo to give a foam residue which is
crystallized from ethyl acetate to give 330 mg of the desired product as a
white crystalline solid, m.p. 265.degree.-267.degree. C.
EXAMPLE 6
N-›4-››4,5-Dihydro
-2-methylpyrazolo›3,4-d!thieno›3,2-b!-azepin-6(2H)-yl!carbonyl!phenyl!cycl
ohexane carboxamide
To an ice bath cooled mixture of 260 mg of
2,4,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo›3,4-d!thieno›3,2-b!az
epine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon is
added 168 .mu.l of triethylamine followed by 134 .mu.l of
cyclohexanecarbonyl chloride. The reaction mixture is stirred at room
temperature for 18 hours under argon. The reaction mixture is evaporated
in vacuo to a residue which is dissolved in 60 ml of methylene chloride
and washed with 20 ml each of water, 1N NaHCO.sub.3, 2 N citric acid and
brine. The organic layer is dried (Na.sub.2 SO.sub.4) and filtered. The
filtrate is passed through a pad of hydrous magnesium silicate and the
filtrate concentrated in vacuo to give a residue which is crystallized
from ethyl acetate to give 185 mg of the desired product as a white
crystalline solid, m.p. 240.degree.-242.degree. C.
EXAMPLE 7
N-›4-››4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!azepin-6(2H)-yl!carbonyl!phen
yl!-2-methylbenzamide
To a solution of 400 mg of
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!azepine
in 12.0 ml of dioxane under argon is added 65 mg of sodium hydride (60% in
mineral oil). After stirring for 15 minutes, 176 .mu.l of o-toluoyl
chloride is added. The reaction mixture is stirred at room temperature for
18 hours under argon. The reaction mixture is evaporated in vacuo to a
residue which is dissolved in 40 ml of methylene chloride and washed with
20 ml each of water and brine. The organic layer is dried (Na.sub.2
SO.sub.4) and filtered. The filtrate is concentrated in vacuo to give a
residue which is purified by chromatography on silica gel plates by
elution with 1:1 ethyl acetate:hexane 100 mg of
N-›4-››4,5-dihydro-2-(2-methylbenzoyl)pyrazolo-›4,3-d!thieno›3,2-b!azepin-
6(2H)-yl!carbonyl!phenyl-2-methylbenzamide as a white foam and 200 mg of
the product as a white foam.
EXAMPLE 8
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2-methylbenzamide
As described for Example 2, 2 mmol of
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido-›3,2-b!azepine
is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride to give the
product as a solid.
As described for Example 8, the following compounds are prepared.
EXAMPLE 9
N-›4-›(4,5Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!pheny
l!-2-fluoro-5-chlorobenzamide
EXAMPLE 10
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!-5-fluoro-2-methylbenzamide
EXAMPLE 11
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!-2-chloropyridine-3-carboxamide
EXAMPLE 12
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,4-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-fluoro-2-methylbenzamide
To a solution of 2 mmol
1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!azepine and 10 mmol of
triethylamine in 25 ml of dichloromethane is added 4.2 mmol of
6-›(5-fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride. After
stirring over the mixture is worked-up as described for Example 1 and the
initial solid treated with 1N NaOH in methanol as described for Example 1
to give the product as a solid.
EXAMPLE 13
N-›5-›(4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-fluoro-2-methylbenzamide
To a solution of 2 mmol of
1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!azepine and 10 mmol of
triethylamine in 25 ml of dichloromethane is added 4.2 mmol of
6-›(5-fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride. After
stirring overnight, the mixture is worked-up as described for Example 1,
and the initial solid treated with 1N NaOH as described for Example 1 to
give the product as a solid.
EXAMPLE 14
N-›4-›(4,10-Dihydro-5H-pyrido›3,2-b!thieno›2,3-e!azepin-5-yl)carbonyl!-3-ch
lorophenyl!-5-fluoro-2-methylbenzamide
To a solution of 2 mmol of
5-(2-chloro-4-aminobenzoyl)-4,10-dihydro-5H-pyrido›3,2-b!thieno›2,3-e!azep
ine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1
mmol of 5-fluoro-2-methyl-benzoyl chloride. After stirring at room
temperature overnight, the mixture is washed with H.sub.2 O, 1M
NaHCO.sub.3 and brine. The solution is dried (Na.sub.2 SO.sub.4) and the
solvent removed to give the product as a solid.
EXAMPLE 15
N-›4-›(6,10-Dihydro-5H-pyrido›3,2-b!thieno›3,2-e!azepin-5-yl)carbonyl!-3-ch
lorophenyl!-5-fluoro-2-methylbenzamide
To a solution of 2 mmol of
5-(2-chloro-4-aminobenzoyl)-6,10-dihydro-5H-pyrido›3,2b-!thieno-›3,2-e!aze
pine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1
mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room
temperature for 16 hours, the solution is washed with H.sub.2 O, 1M
NaHCO.sub.3 and brine. The solution is dried (Na.sub.2 SO.sub.4) and the
solvent removed to give the product as a solid.
EXAMPLE 16
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!phen
yl!-5-fluoro-2-methylbenzamide
As described for Example 1, a solution of 2 mmol of
4-(4-aminobenzoyl)-4,5-dihydropyrazolo›3,4-d!-pyrido›2,3-b!azpeine and 10
mmol of triethylamine is stirred with 4.2 mmol of 5-fluoro-2-methylbenzoyl
chloride in dichloromethane to give a solid. The solid is stirred with 1N
NaOH in methanol and the mixture worked-up as for Example 1 to give the
product as a solid.
EXAMPLE 17
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-2-p
yridinyl!-5-fluoro-2-methylbenzamide
As described for Example 13, 4,5-dihydropyrazolo›3,4-d!pyrido›2,3-b!azepine
is reacted with 6-›(5-fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl
chloride to give the product as a solid.
EXAMPLE 18
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl!carbonyl!phen
yl!›1,1'-biphenyl!-2-carboxamide
As described for Example 1, a solution of 2 mmol of
4-(4-aminobenzoyl)-4,5-dihydropyrazolo›3,4-d!-pyrido›2,3-b!azepine and 10
mmol of triethylamine is stirred with›1,1'-biphenyl!-2-carbonyl chloride
in dichloromethane for 16 hours at room temperature. The initial solid is
stirred with 1N NaOH in methanol as described in Example 1 to give the
product as a solid.
EXAMPLE 19
N-›5-›(4,5-Dihydropyrazolo›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)
carbonyl!-2-pyridinyl!›1,1'-biphenyl!-2-carboxamide
As described for Example 13, a solution of 2.0 mmol of
4,5-dihydropyrazolo›3,4-d!pyrido›2,3-b!azepine and 10 mmol of
triethylamine is stirred with 4.2 mmol of
6-›(5-fluoro-2-methylbenzoyl)amino!pyridine-3-carbonyl chloride in
dichloromethane at room temperature for 16 hours to give the product as a
solid.
EXAMPLE 20
N-4-›(4,5-Dihydropyrazol›3,4-d!pyrido›2,3-b!azepin-6(1H)-yl)carbonyl!-3-phe
nyl!-5-fluoro-2-methylbenzamide
As described for Example 2, a solution of 2 mmol of
4-(2-chloro-4-aminobenzoyl)-4,5-dihydropyrazolo-›3,4-d!pyrido›2,3-b!azepin
e and 10 mmol of triethylamine is stirred with 4.2 mmol of
5-fluoro-2-methylbenzoyl chloride in dichloromethane at room temperature
to give a solid. The solid is stirred with 1N NaOH in methanol as
described for Example 2 to give the product as a solid.
The following compounds are prepared as described for Example 1 (Table A).
TABLE A
______________________________________
##STR98##
Ex. No. R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
21 Cl H H H H H
22 Cl H H H H Cl
23 Cl H Cl H H H
24 Cl H Cl H H Cl
25 Cl H H Cl H H
26 Cl H H Cl H Cl
27 F H H Cl H H
28 F H H Cl H Cl
29 CH.sub.3 H H H H H
30 CH.sub.3 H H H H Cl
31 CH.sub.3 CH.sub.3
H H H H
32 CH.sub.3 CH.sub.3
H H H Cl
33 OCH.sub.3 H H H H H
34 OCH.sub.3 H H H H Cl
35 OCF.sub.3 H H H H H
36 OCF.sub.3 H H H H Cl
37 Cl H H H Cl H
38 Cl H H H Cl Cl
39 CH.sub.3 H H H CH.sub.3
H
40 CH.sub.3 H H H CH.sub.3
Cl
41 SCH.sub.3 H H H H H
42 SCH.sub.3 H H H H Cl
43 CF.sub.3 H H H H H
44 CF.sub.3 H H H H Cl
45 CF.sub.3 H F H H H
46 CF.sub.3 H F H H Cl
47 Cl H H F H H
48 Cl H H F H Cl
49 NO.sub.2 H H H H H
50 NO.sub.2 H H H H Cl
51 NH.sub.2 H H H H H
52 NH.sub.2 H H H H Cl
53 N(CH.sub.3).sub.2
H H H H H
54 N(CH.sub.3).sub.2
H H H H Cl
55 OCH.sub.3 H H Cl H H
56 OCH.sub.3 H H H H Cl
57 Cl Cl H H H H
58 Cl Cl H H H Cl
59 CF.sub.3 H H H F H
60 Cl Cl H Cl H H
61 NHCH.sub.3
H H H H H
62 NHCH.sub.3
H H H H Cl
63 H CF.sub.3
H H H H
64 H CF.sub.3
H H H Cl
______________________________________
As described for Example 1, the following compounds are prepared (Table B).
TABLE B
______________________________________
##STR99##
Ex. No
R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
65 CH.sub.3 H H H H H
66 CH.sub.3 H H F H H
67 CH.sub.3 F H H H H
68 H OCH.sub.3
OCH.sub.3
OCH.sub.3
H H
69 Cl H H H H H
70 F H F H H H
71 Br H H H H H
72 Cl H F H H H
73 Ph H H H H H
74 Cl H H Br H H
75 CH.sub.3 H H H H Br
76 CH.sub.3 H H F H Cl
77 Cl H H Cl H H
78 CH.sub.3 CH.sub.3
H H H H
79 Cl H H F H H
80 Cl H H CF.sub.3
H H
81 Cl H H H F H
82 Cl H H H Cl H
83 Cl H H F H H
84
##STR100##
H H H H H
85
##STR101##
H H H H H
86 CH.sub.3 H H H CH.sub.3
H
87 Cl H H F H Cl
88 Cl H F H H Cl
89 Cl Cl H H H H
90 Cl H H Cl H H
91 OCH.sub.3 H H H H H
92 OCF.sub.3 H H H H H
93 CF.sub.3 H H H H H
94 Cl Cl H Cl H H
95 SCH.sub.3 H H H H H
96 Cl H NO.sub.2
H H H
97 CH.sub.3 H H CH.sub.3
H H
98 F H H Cl H H
99 Cl H H NH.sub.2
H H
100 F CF.sub.3
H H H H
101 OCH.sub.3 H H Cl H H
102 Cl H H SCH.sub.3
H H
103 F H H H CF.sub.3
H
104 F H CF.sub.3
H H H
105 CF.sub.3 H F H H H
106 NO.sub.2 H H H H H
107 F H H H H H
108 Cl H NH.sub.2
H H H
______________________________________
The following compounds are prepared as described in Example 2 (Table C).
TABLE C
______________________________________
##STR102##
Ex. No R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
109 Cl H H H H H
110 Cl H H H H Cl
111 Cl H Cl H H H
112 Cl H Cl H H Cl
113 Cl H H Cl H H
114 Cl H H Cl H Cl
115 F H H Cl H H
116 F H H Cl H Cl
117 CH.sub.3 H H H H H
118 CH.sub.3 H H H H Cl
119 CH.sub.3 CH.sub.3
H H H H
120 CH.sub.3 CH.sub.3
H H H Cl
121 OCH.sub.3 H H H H H
122 OCH.sub.3 H H H H Cl
123 OCF.sub.3 H H H H H
124 OCF.sub.3 H H H H Cl
125 Cl H H H Cl H
126 Cl H H H Cl Cl
127 CH.sub.3 H H H CH.sub.3
H
128 CH.sub.3 H H H CH.sub.3
Cl
129 SCH.sub.3 H H H H H
130 SCH.sub.3 H H H H Cl
131 CF.sub.3 H H H H H
132 CF.sub.3 H H H H Cl
133 CF.sub.3 H F H H H
134 CF.sub.3 H F H H Cl
135 Cl H H F H H
136 Cl H H F H Cl
137 NO.sub.2 H H H H H
138 NO.sub.2 H H H H Cl
139 NH.sub.2 H H H H H
140 NH.sub.2 H H H H Cl
141 N(CH.sub.3).sub.2
H H H H H
142 N(CH.sub.3).sub.2
H H H H Cl
143 OCH.sub.3 H H Cl H H
144 OCH.sub.3 H H H H Cl
145 Cl Cl H H H H
146 Cl Cl H H H Cl
147 CF.sub.3 H H H F H
148 Cl Cl H Cl H H
149 NHCH.sub.3
H H H H H
150 NHCH.sub.3
H H H H Cl
151 H CF.sub.3
H H H H
152 H CF.sub.3
H H H Cl
______________________________________
As described for Example 2, the following compounds are prepared.
TABLE D
______________________________________
##STR103##
Ex No. R.sub.1 R.sub.2 R.sub.3
R.sub.4 R.sub.5
A
______________________________________
153 CH.sub.3 H H H H C
154 CH.sub.3 H H H H N
155 CH.sub.3 H H CH.sub.3
H C
156 Cl H H H H C
157 Cl H H H Cl C
158 Cl H H H H N
159 Cl H Cl H H C
160 Cl H Cl H H N
161 Cl H H F H C
162 OCH.sub.3 H H H H C
163 OCH.sub.3 H H H H N
164 OCH.sub.3 H H Cl H C
165 OCH.sub.3 H H OCH.sub.3
H C
166 OCH.sub.3 H H OCH.sub.3
H N
167 OCH.sub.3 H H Cl H N
168 CH.sub.3 F H H H C
169 H F H H H N
170 CH.sub.3 CH.sub.3 H H H C
171 Cl Cl H H H C
172 Cl Cl H H H N
173 F Cl H H H C
174 F H Cl H H N
175 SCH.sub.3 H H H H C
176 SCH.sub.3 H H H H N
177 F H H Cl H C
178 F H H Cl H N
179 F H H H Cl C
180 H CF.sub.3 H H H C
181 H CF.sub.3 H H H N
182 CF.sub.3 H H H H C
183 OCF.sub.3 H F H H C
184 CH.sub.3 H H F H C
______________________________________
As described for Example 5, the following compounds are prepared (Table E).
TABLE E
______________________________________
##STR104##
Ex. No.
R.sub.1 R.sub.2 R.sub.3
R.sub.4 R.sub.5
X
______________________________________
185 CH.sub.3 H H H H H
186 CH.sub.3 H H F H H
187 CH.sub.3 F H H H H
188 CH.sub.2 Ph
H H H H Cl
189 Cl H H H H H
190 F H F H H H
191 Br H H H H H
192 Cl H F H H H
193 Ph H H H H H
194 Cl H H Br H H
195 CH.sub.3 H H H H Br
196 CH.sub.3 H H F H Cl
197 Cl H H Cl H H
198 CH.sub.3 CH.sub.3
H H H H
199 Cl H H F H H
200 Cl H H CF.sub.3
H H
201 Cl H H H F H
202 Cl H H H Cl H
203 Cl H H F H H
204
##STR105##
H H H H H
205
##STR106##
H H H H H
206 CH.sub.3 H H H CH.sub.3
H
207 Cl H H F H Cl
208 Cl H F H H Cl
209 Cl Cl H H H H
210 Cl H H Cl H H
211 OCH.sub.3 H H H H H
212 OCF.sub.3 H H H H H
213 CF.sub.3 H H H H H
214 Cl Cl H Cl H H
215 SCH.sub.3 H H H H H
216 Cl H NO.sub.2
H H H
217 CH.sub.3 H H CH.sub.3
H H
218 F H H Cl H H
219 Cl H H NH.sub.2
H H
220 F CF.sub.3
H H H H
221 OCH.sub.3 H H Cl H H
222 Cl H H SCH.sub.3
H H
223 F H H H CF.sub.3
H
224 F H CF.sub.3
H H H
225 CF.sub.3 H F H H H
226 NO.sub.2 H H H H H
227 F H H H H H
228 Cl H NH.sub.2
H H H
______________________________________
As described for Example 5, the following compounds are prepared (Table F).
TABLE F
______________________________________
##STR107##
Ex. No.
R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
229 CH.sub.3 H H H H H
230 CH.sub.3 H H F H H
231 CH.sub.3 F H H H H
232 CH.sub.2 Ph
H H H H Cl
233 Cl H H H H H
234 F H F H H H
235 Br H H H H H
236 Cl H F H H H
237 Ph H H H H H
238 Cl H H Br H H
239 CH.sub.3 H H H H Br
240 CH.sub.3 H H F H Cl
241 Cl H H Cl H H
242 CH.sub.3 CH.sub.3
H H H H
243 Cl H H F H H
244 Cl H H CF.sub.3
H H
245 Cl H H H F H
246 Cl H H H Cl H
247 Cl H H F H H
248
##STR108##
H H H H H
249
##STR109##
H H H H H
250 CH.sub.3 H H H CH.sub.3
H
251 Cl H H F H Cl
252 Cl H F H H Cl
253 Cl Cl H H H H
254 Cl H H Cl H H
255 OCH.sub.3 H H H H H
256 OCF.sub.3 H H H H H
257 CF.sub.3 H H H H H
258 Cl Cl H Cl H H
259 SCH.sub.3 H H H H H
260 Cl H NO.sub.2
H H H
261 CH.sub.3 H H CH.sub.3
H H
262 F H H Cl H H
263 Cl H H NH.sub.2
H H
264 F CF.sub.3
H H H H
265 OCH.sub.3 H H Cl H H
266 Cl H H SCH.sub.3
H H
267 F H H H CF.sub.3
H
268 F H CF.sub.3
H H H
269 CF.sub.3 H F H H H
270 NO.sub.2 H H H H H
271 F H H H H H
272 Cl H NH.sub.2
H H H
______________________________________
As described for Example 2, the following compounds are prepared (Table G).
TABLE G
______________________________________
##STR110##
Ex. No.
R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
273 CH.sub.3 H H H H H
274 CH.sub.3 H H F H H
275 CH.sub.3 F H H H H
276 CH.sub.2 Ph
H H H H Cl
277 Cl H H H H H
278 F H F H H H
279 Br H H H H H
280 Cl H F H H H
281 Ph H H H H H
282 Cl H H Br H H
283 CH.sub.3 H H H H Br
284 CH.sub.3 H H F H Cl
285 Cl H H Cl H H
286 CH.sub.3 CH.sub.3
H H H H
287 Cl H H F H H
288 Cl H H CF.sub.3
H H
289 Cl H H H F H
290 Cl H H H Cl H
291 Cl H H F H H
292
##STR111##
H H H H H
293
##STR112##
H H H H H
294 CH.sub.3 H H H CH.sub.3
H
295 Cl H H F H Cl
296 Cl H F H H Cl
297 Cl Cl H H H H
298 Cl H H Cl H H
299 OCH.sub.3 H H H H H
300 OCF.sub.3 H H H H H
301 CF.sub.3 H H H H H
302 Cl Cl H Cl H H
303 SCH.sub.3 H H H H H
304 Cl H NO.sub.2
H H H
305 CH.sub.3 H H CH.sub.3
H H
306 F H H Cl H H
307 Cl H H NH.sub.2
H H
308 F CF.sub.3
H H H H
309 OCH.sub.3 H H Cl H H
310 Cl H H SCH.sub.3
H H
311 F H H H CF.sub.3
H
312 F H CF.sub.3
H H H
313 CF.sub.3 H F H H H
314 NO.sub.2 H H H H H
315 F H H H H H
316 Cl H NH.sub.2
H H H
______________________________________
As described for Example 2, the following compounds are prepared (Table H).
TABLE H
______________________________________
##STR113##
Ex. No.
R.sub.1 R.sub.2 R.sub.3
R.sub.4
R.sub.5
X
______________________________________
317 CH.sub.3 H H H H H
318 CH.sub.3 H H F H H
319 CH.sub.3 F H H H H
320 CH.sub.2 Ph
H H H H Cl
321 Cl H H H H H
322 F H F H H H
323 Br H H H H H
324 Cl H F H H H
325 Ph H H H H H
326 Cl H H Br H H
327 CH.sub.3 H H H H Br
328 CH.sub.3 H H F H Cl
329 Cl H H Cl H H
330 CH.sub.3 CH.sub.3
H H H H
331 Cl H H F H H
332 Cl H H CF.sub.3
H H
333 Cl H H H F H
334 Cl H H H Cl H
335 Cl H H F H H
336
##STR114##
H H H H H
337
##STR115##
H H H H H
338 CH.sub.3 H H H CH.sub.3
H
339 Cl H H F H Cl
340 Cl H F H H Cl
341 Cl Cl H H H H
342 Cl H H Cl H H
343 OCH.sub.3 H H H H H
344 OCF.sub.3 H H H H H
345 CF.sub.3 H H H H H
346 Cl Cl H Cl H H
347 SCH.sub.3 H H H H H
348 Cl H NO.sub.2
H H H
349 CH.sub.3 H H CH.sub.3
H H
350 F H H Cl H H
351 Cl H H NH.sub.2
H H
352 F CF.sub.3
H H H H
353 OCH.sub.3 H H Cl H H
354 Cl H H SCH.sub.3
H H
355 F H H H CF.sub.3
H
356 F H CF.sub.3
H H H
357 CF.sub.3 H F H H H
358 NO.sub.2 H H H H H
359 F H H H H H
360 Cl H NH.sub.2
H H H
______________________________________
EXAMPLE 361
N-›4-›(4.5-Dihydro-2-methylpyrazolo›3,4-d!thieno›3,2-blazepin-6(2H)-yl)carb
onyl!phenyl!-2-methylbenzamide
As described for Example 5,
2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo›3,4-d!-thieno›3,2-b
!azepine is reacted with 2-methylbenzoyl chloride to give the product as
crystals (from ethyl acetate), m.p. 257.degree.-260.degree. C.
EXAMPLE 362
N-›4-›(4,5-Dihydropyrazolo›3,4-d!thieno›3,2-b!blazepin-6(1H)-yl)carbonyl!ph
enyl!›1,1'-biphenyl!-2-carboxamide
As described for Example 2,
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!thieno›3,2-b!-azepine
(297 mg) is reacted with 0.542 g of ›1,1'-biphenyl!-2-carbonyl chloride to
give 0.70 g of bis acylated product. A mixture of this product in 13 ml of
tetrahydrofuran-methanol (9:4) and 2.3 ml of 1N NaOH is stirred for 18
hours at room temperature. To the mixture is added 2.3 ml of 1N HCl and
the solvent removed. The mixture is triturated with 50 ml of CH.sub.2
Cl.sub.2, filtered and the solid washed with CH.sub.2 Cl.sub.2 and water
to give 0.27 g of off-white crystals, m.p. 280.degree.-284.degree. C.
EXAMPLE 363
N-›4-›(4,5-Dihydro-6H-isoxazolo›5,4-d!thieno›3,2-b!-azepin-6-yl)carbonyl!ph
enyl!-5-fluoro-2-methylbenzamide
As described for Example 1, a solution of 2 mmol of
5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo ›5,4-d!thieno›3,2-b!azepine
and 5 mmol of triethylamine is reacted with 2.2 mmol of
5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane under argon
for 16 hours to give the product as a solid.
EXAMPLE 364
6-(›1,1'-Biphenyl!-4-yl
carbonyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!azepine
A mixture of 0.186 g of
1,4,5,6-tetrahydropyrazolo›3,4-d!-6H-pyrido›3,2-b!azepine, 0.492 g of
4-›1,1'-biphenyl!carbonyl chloride, and 0.365 g of
N.N-diisopropylethylamine in 9 ml of dichloromethane and 1 ml of
tetrahydrofuran is stirred at room temperature for 24 hours. The solution
is poured into water and extracted with dichloromethane. The extract is
washed with H.sub.2 O, 2N NaHCO.sub.3, brine and dried (Na.sub.2
SO.sub.4). The solvent is removed under vacuum and the residue dissolved
in 45 ml of methanol-tetrahydrofuran (2:1) and 4.5 ml of 1M NaOH added.
The solution is stirred at room temperature overnight, concentrated under
vacuum. To the residue is added 100 ml of H.sub.2 O and the mixture
acidified with 2N citric acid (pH ca 5). The mixture is extracted with
chloroform and the extract washed with 1N NaHCO.sub.3, H.sub.2 O, brine
and dried (Na.sub.2 SO.sub.4). The solution is filtered through a thin pad
of hydrous magnesium silicate and the filtrate concentrated to dryness.
The residue (0.31 g) is chromatographed on silica gel with
dichloromethane-ethyl acetate (6:4) as solvent to give 0.075 g of solid,
m.p. 205.degree.-206.degree. C.
EXAMPLE 365
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phen
yl!›1,1'-biphenyl!-2-carboxamide
A mixture of 0.23 g of
6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!azepine,
0.375 g of 4-›1,1'-biphenyl!carbonyl chloride and 0.224 g of
N,N-diisopropylethylamine in 5 ml of dichloromethane and 1 ml of
tetrahydrofuran is stirred at room temperature for 6 hours. The solvent is
removed and the residue dissolved in 80 ml of chloroform. The solution is
washed 2 times each with 1N NaHCO.sub.3, H.sub.2 O, brine and dried
(Na.sub.2 SO.sub.4). The solution is filtered through a thin pad of
hydrous magnesium silicate and the filter pad washed with ethyl acetate.
The filtrate is concentrated to dryness under vacuum. To the residue (0.64
g) in 6 ml of methanol-tetrahydrofuran (1:1) is added 2.0 mmol of 1M NaOH
and the mixture stirred at room temperature for 2 hours. To the mixture is
added 10 ml of tetrahydrofuran-methanol (1:1) and the mixture stirred for
2 hours. The volatiles are removed under vacuum, H.sub.2 O added and the
mixture acidified with acetic acid. The mixture is extracted with
dichloromethane and the extract washed with H.sub.2 O, brine and dried
(Na.sub.2 SO.sub.4). The solvent is removed and the residue heated with
hexane (700 ml) and filtered. The insoluble solid is crystallized from
CH.sub.2 Cl.sub.2 -hexane to give 0.25 g of white crystals, mp
250.degree.-251.degree. C.
EXAMPLE 366
N-›4-›(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-3-c
hlorophenyl!›1,1'-biphenyl!-2-carboxamide
A mixture of 0.3 g of
6-(4-amino-2-chlorobenzoyl)-1,4,5,6-tetrahydropyrazolo›3,4-d!pyrido›3,2-b!
azepine, 0.52 g of 4-›1,1'-biphenyl!carbonyl chloride and 0.5 g of
N,N-diisopropylethylamine in 10 ml of dichloromethane and 2 ml of
tetrahydrofuran is stirred at room temperature for 24 hours. The solvent
is removed and to the residue is added 10 ml of methanol and 5 mmol of 1N
NaOH. The mixture is stirred overnight, concentrated under vacuum and
diluted with water. The mixture is extracted with dichloromethane and the
extract washed with 2N NaHCO.sub.3, H.sub.2 O, brine and dried (Na.sub.2
SO.sub.4). The solvent is removed under vacuum to give the product as a
solid (glass), m.p. 181.degree.-192.degree. C.
EXAMPLE 367
N-›4-›4(4,5-Dihydropyrazolo›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!phe
nyl!-5-fluoro-2-methylbenzamide
As mixture of 2 mmol of
1,4,5,6-tetrahydropyrazolo›3,4-d!-6H-pyrido›3,2-b!azepine, 5 mmol of
N,N-diisopropylethylamine and 2 mmol of
4-›(5-fluoro-2-methylbenzoyl)amino!benzoyl chloride in 20 ml of
dichloromethane is stirred at room temperature for 16 hours. The solvent
is removed and the residue dissolved in 25 ml of methanol and 5 mmol of 2N
NaOH added. The mixture is stirred at room temperature overnight and the
volatiles removed under vacuum. The mixture is diluted with water and
extracted with dichloromethane, the extract washed with H.sub.2 O,
2NNaHCO.sub.3, H.sub.2 O, brine and dried (Na.sub.2 SO.sub.4). The solvent
is removed to give the product as a solid, mp 175.degree.-188.degree. C.
EXAMPLE 368
N-›5-›(4,5-Dihydro›3,4-d!pyrido›3,2-b!azepin-6(1H)-yl)carbonyl!-2-pyridinyl
!›1,1'-biphenyl!-2-carboxamide
To a solution of 0.233 g of
1,4,5,6-tetrahydropyrazolo›3,4-d!-6H-pyrido›3,2-b!azepine, 0.355 g of
N,N-diisopropylamine in 7 ml of dichloromethane is added 0.026 g of
6-››1,1'-biphenyl!-2-carbonyl!amino pyridine-3-carbonyl chloride in 5 ml
of dichloromethane and the mixture stirred for 5 hours. The solvent is
removed and the residue dissolved in 15 ml of tetrahydrofuran --CH.sub.3
OH (1:1) and 2.5 ml of 2N NaOH. The solution is stirred at room
temperature overnight and the solvent removed. To the residue is added 2N
citric acid and the mixture extracted with CH.sub.2 Cl.sub.2. The extract
is washed with H.sub.2 O, dried (Na.sub.2 SO.sub.4) and the solvent
removed to give a solid. The solid is purified by thick layer
chromatography on silica gel with ethyl acetate as solvent to give 0.064 g
of solid, as a glass, m.p. 160.degree.-185.degree. C.
The subject compounds of the present invention are tested for biological
activity.
Binding Assay to Rat Hepatic V.sub.1 Receptors
Rat liver plasma membranes expressing the vasopressin V.sub.1 receptor
subtypes are isolated by sucrose density gradient according to the method
described by Lesko et al., (1973). These membranes are quickly suspended
in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin
(BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at
-70.degree. C. until used in subsequent binding experiments. For binding
experiments, the following is added to the wells of a ninety-six well
format microtiter plate: 100 .mu.l of 100.0 mM Tris.HCl buffer containing
10.0 mM MgCl.sub.2, 0.2% heat inactivated BSA and a mixture of protease
inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %, 1,10-phenanthroline,
2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 .mu.l of
›phenylalanyl-3,4,5-.sup.3 H! vasopressin (S.A. 45.1 Ci/mmole) at 0.8 nM,
and the reaction initiated by the addition of 80 .mu.l of tissue membranes
containing 20 .mu.g of tissue protein. The plates are kept undisturbed on
the bench top at room temperature for 120 min. to reach equilibrium.
Non-specific samples are assayed in the presence of 0.1 .mu.M of the
unlabeled antagonist phenylalanylvasopressin, added in 20.0 .mu.l volume
to a final incubation volume of 200 .mu.l. Upon completion of binding, the
content of each well is filtered off, using a Brandel.RTM. cell Harvester
(Gaithersburg, Md.). The radioactivity trapped on the filter disk by the
ligand-receptor complex is assessed by liquid scintillation counting in a
Packard LS Counter, with an efficiency of 65% for tritium. The data are
analyzed for IC.sub.50 values by the LUNDON-2 program for competition
(LUNDON SOFTWARE, Ohio).
Binding Assay to Rat Kidney Medullary V.sub.2 Receptors
Medullary tissues from rat kidneys are dissected out, cut into small pieces
and let soak in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA
with many changes of the liquid phase, until the solution is clear of
blood. The tissue is homogenized in a 0.25M sucrose solution containing
1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a
teflon pestle. The homogenate is filtered through several layers (4
layers) of cheese cloth. The filtrate is rehomogenized using a dounce
homogenizer, with a tight fitting pestle. The final homogenate is
contrifuged at 1500.times.g for 15 min. The nuclear pellet is discarded
and the supernatant fluid recentrifuged at 40,000.times.g for 30 min. The
resulting pellet formed contains a dark inner part with the exterior,
slightly pink. The pink outer part is suspended in a small amount of 50.0
mM Tris.HCl buffer, pH 7.4. The protein content is determined by the
Lowry's method (Lowry et al, J. Biol. Chem., 1953). The membrane
suspension is stored at -70.degree. C., in 50.0 mM Tris.HCl, containing
0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0
mg protein per ml of suspension until use in subsequent binding
experiments.
For binding experiments, the following is added in .mu.l volume to wells of
a 96 well format of a microtiter plate: 100.0 .mu.l of 100.0 mM Tris.HCl
buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl.sub.2 and a
mixture of protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;
1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM
PMSF, 20.0 .mu.l of ›.sup.3 H!Arginine.sup.8, vasopressin (S.A. 75.0
Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0
.mu.l of tissue membranes (200.0 .mu.g tissue protein). The plates are
left undisturbed on the bench top for 120 min. to reach equilibrium.
Non-specific binding is assessed in the presence of 1.0 .mu.M of unlabeled
ligand, added in 20 .mu.l volume. For test compounds, these are
solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 .mu.l volume
to a final incubation volume of 200 .mu.l. Upon completion of binding, the
content of each well is filtered off, using a Brandel.RTM. cell Harvester
(Gaithersburg, Md.). The radioactivity trapped on the filter disk by the
ligand-receptor complex is assessed by liquid scintillation counting in a
Packard LS Counter, with an efficiency of 65% for tritium. The data are
analyzed for IC.sub.50 values by the LUNDON-2 program for competition
(LUNDON SOFTWARE, Ohio).
Radioligand Binding Experiments with Human Platelet Membranes
Platelet Source: Hudson Valley Blood Services, Westchester Medical Center,
Valhalla, N.Y.
Platelet Membrane Preparation:
Frozen platelet rich plasma (PRP), received from the Hudson Valley Blood
Services are thawed to room temperature. The tubes containing the PRP are
centrifuged at 16,000.times.g for 10 min. at 4.degree. C. and the
supernatant fluid discarded. The platelets resuspended in an equal volume
of 50.0 mM Tris.HCl, pH 7.5 containing 120 mM NaCl and 20.0 mM EDTA. The
suspension is recentrifuged at 16,000.times.g for 10 min. This washing
step is repeated one more time. The wash is discarded and the lysed
pellets homogenized in low ionic strength buffer of Tris.HCl, 5.0 mM, pH
7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at
39,000.times.g for 10 min. The resulting pellet is resuspended in Tris.HCl
buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000.times.g for 10 min.
The final pellet is resuspended in 50.0 mM Tris.HCl buffer pH 7.4
containing 120 mM NaCl and 5.0 mM HCl to give 1.0-2.0 mg protein per ml of
suspension.
Binding to Vasopressin V.sub.1 Receptor Subtype in Human Platelet
Membranes:
In wells of a 96 well format microtiter plate, add 100 .mu.l of 50.0 mM
Tris.HCl buffer containing 0.2% BSA and a mixture of protease inhibitors
(aprotinin, leupeptin etc.). Then add 20 .mu.l of ›.sup.3 H!Ligand:
(Manning or Arg.sup.8 Vasopressin), to give final concentrations ranging
from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 .mu.l of
platelet suspension (approx. 100 .mu.g protein). Mix all reagents by
pipetting the mixture up and down a few times. Non-specific binding is
measured in the presence of 1.0 .mu.M of unlabeled ligand (Manning or
Arg.sup.8 Vasopressin). Let the mixture stand undisturbed at room
temperature for ninety (90) min. Upon this time, rapidly filter off the
incubate under vacuum suction over GF/B filters, using a Brandel.RTM.
Harvester. Determine the radioactivity caught on the filter disks by the
addition of liquid scintillant and counting in a liquid scintillator
Binding to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfected with
the cDNA expressing the Human V.sub.2 Vasopressin Receptor
Membrane Preparation
Flasks of 175 ml capacity, containing attached cells grown to confluence
are cleared of culture medium by aspiration. The flasks containing the
attached cells are rinsed with 2.times.5 ml of phosphate buffered saline
(PBS) and the liquid aspirated off each time. Finally, 5 ml of an enzyme
free dissociation Hank's based solution (Specialty Media, Inc., Lafayette,
N.J.) is added and the flasks are left undisturbed for 2 min. The content
of all flasks is poured into a centrifuge tube and the cells pelleted at
300.times.g for 15 min. The Hank's based solution is aspirated off and the
cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM
Tris.HCl buffer, pH 7.4 containing 0.25M sucrose and 1.0 mM EDTA. The
homogenate is centrifuged at 1500.times.g for 10 min to remove ghost
membranes. The supernatant fluid is centrifuged at 100,000.times.g for 60
min to pellet the receptor protein. Upon completion, the pellet is
resuspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4. The
protein content is determined by the Lowry method and the receptor
membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM
phenylmethylsulfonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to
give 2.5 mg receptor protein per ml of suspension.
Receptor Binding
For binding experiments, the following is added in .mu.l volume to wells of
a 96 well format of a microtiter plate: 100.0 .mu.l of 100.0 mM Tris.HCl
buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl.sub.2 and a
mixture of protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %;
1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM
PMSF, 20.0 .mu.l of ›.sup.3 H!Arginine.sup.8, vasopressin (S.A. 75.0
Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0
.mu.l of tissue membranes (200.0 .mu.g tissue protein). The plates are
left undisturbed on the bench top for 120 min to reach equilbrium.
Non-specific binding is assessed in the presence of 1.0 .mu.M of unlabeled
ligand, added in 20 .mu.l volume. For test compounds, these are
solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 .mu.l volume
to a final incubation volume of 200 .mu.l. Upon completion of binding, the
content of each well is filtered off, using a Brandel.RTM. cell Harvester
(Gaithersburg, Md.). The radioactivity trapped on the filter disk by the
ligand-receptor complex is assessed by liquid scintillation counting in a
Packard LS Counter, with an efficiency of 65% for tritium. The data are
analyzed for IC.sub.50 values by the LUNDON-2 program for competition
(LUNDON SOFTWARE, Ohio).
Vasopressin V.sub.2 Antagonist Activity in Conscious Hyrdated Rats
Conscious hydrated rats are treated with compounds under study from 0.1 to
100 mg/kg orally or vehicle. Two to four rats are used for each compound.
One hour later, arginine vasopressin (AVP, antidiuretic hormone, ADH)
dissolved in peanut oil is administered at 0.4 .mu.g/kg intraperitoneally.
Two rats in each test would not receive arginine vasopressin but only the
vehicle (peanut oil) to serve as water-loading control. Twenty minutes
later each rat is given 30 mL/kg of deionized water orally by gavage and
is placed individually in a metabolic cage equipped with a funnel and a
graduated glass cylinder to collect urine for four hours. Urine volume is
measured and osmolality analyzed by use of a Fiske One-Ten osmometer
(Fiske Assoc., Norwood, Mass. U.S.A.). Urinary sodium, potassium, and
chloride are analyzed by use of ion-specific electrodes in a Beckman
E3(Electrolyte 3) Analyzer.
In the following results, decreased urine volume and decreased osmolality
relative to AVP-control indicates activity. The results of this test on
representative compounds of this invention are shown in Table 2.
Vasopressin V.sub.1 Antagonist Activity in Conscious Rats
Conscious rats are restrained in a supine position with elastic tape. The
area at the base of the tail is locally anesthetized by subcutaneous
infiltration with 2% procaine (0.2 ml). Using aseptic technique the
ventral caudal tail artery is isolated and a cannula made of PE 10 and 20
(heat-fused) tubing is passed into the lower abdominal aorta. The cannula
is secured, heparinized (1000 i.u./cc), sealed and the would closed with
one or two stitches of Dexon 4-0. The caudal vein is also cannulated in
the same manner for intravenous drug administration. The duration of the
surgery is approximately 5 minutes. Additional local anesthesia (2%
procaine or lidocaine) is provided as needed.
The animals are placed in plastic restraining cages in an upright position.
The cannula is attached to a Starham P23Db pressure transducer and
pulsatile blood pressure is recorded. Increase of systolic blood pressure
responses to arginine vasopressin 0.01 and 0.2 international unit (I.U.)
(350 I.U.=1 mg) injections are recorded prior to any drug (compound)
administration, after which each rat is dosed orally with compounds under
study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30 mg/kg (1 cc/kg).
The vasopressin injections are repeated 30,60,90,120,180,240 and 300 min.
later. Percentage of antagonism by the compound is calculated using the
pre-drug vasopressin vasopressor response as 100%.
TABLE 1
______________________________________
Binding Assay to Rat Hepatic V.sub.1 Receptors and Rat Kidney
Medullary V.sub.2 Receptors or *Binding to V.sub.1 Receptor
Subtype in Human Platelet and **Binding to Membranes of
Mouse Fibroblast Cell Line (LV-2) Transfected with the
cDNA Expressing the Human V.sub.2 Receptor
##STR116##
Ex. IC.sub.50 (.mu.M)
No. R R.sub.1
Ar A V.sub.1
V.sub.2
______________________________________
361 CH.sub.3
H
##STR117##
CH
##STR118##
##STR119##
5 CH.sub.3
H
##STR120##
CH
##STR121##
##STR122##
6 CH.sub.3
H
##STR123##
CH 4.7 0.23
7 H H
##STR124##
CH
##STR125##
##STR126##
1 H H
##STR127##
CH 2.0 0.34
2 H H
##STR128##
CH 1.7
##STR129##
3 H Cl
##STR130##
CH
##STR131##
0.0061
4 H Cl
##STR132##
CH
##STR133##
0.036
______________________________________
TABLE 1a
______________________________________
Binding Assay to Rat Hepatic V.sub.1 Receptors and Rat Kidney
Medullary V.sub.2 Receptors or *Binding to V.sub.1 Receptors
Subtype in Human Platelet and **Binding to Membranes of
Mouse Fibroblast Cell Line (LV-2) Transfected with the
cDNA Expressing the Human V.sub.2 Receptor
IC.sub.50 (.mu.M)
IC.sub.50 (.mu.M)
Ex. No. V.sub.1 V.sub.2
______________________________________
364 *77% at 10 .mu.M
17% at 1 .mu.M
365 *0.101 0.0016
367 *0.31 0.03
16 *3.3 0.55
______________________________________
TABLE 2
______________________________________
Vasopressin V.sub.2 Antagonist Activity iin Conscious Hydrated
Rats
Dose Urine Vol.
Osmolality
Ex. No. (mg/kg) N (ml/4 hrs.)
(mOsm/kg)
______________________________________
* 78 13.3 .+-. 0.3
229 .+-. 6
** 6 12.1 .+-. 1
497 .+-. 53
4 12.4 .+-. 0.8
361 .+-. 30
*** 76 2 .+-. 0.2
1226 .+-. 58
1 10 2 15.3 535
2 10 2 17.8 429
7 10 2 20.8 322
365 10 2 2.6 251
366 10 2 17.8 431
367 10 2 10 627
368 10 2 20.3 371
______________________________________
*Water-load control
**Waterload
Control + DMSO (10%)
(20%)
***AVPcontrol
Oxytocin Receptor Binding
(a) Membrane Preparation
Female Sprague-Dawley rats weighing approximately 200-250 g are injected
intramuscularly (i.m.) with 0.3 mg/kg of body weight of diethylstilbestrol
(DES). The rats are sacrificed 18 hours later under pentobarbital
anesthesia. The uteri are dissected out, cleaned of fat and connective
tissues and rinsed in 50 ml of normal saline. The tissue pooled from six
rats is homogenized in 50 ml of 0.01 mM TriS.HCl, containing 0.5 mM
dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at
setting 6 with three passes of 10 sec each. The homogenate is passed
through two (2) layers of cheesecloth and the filtrate contrifuged at
1000.times.g for 10 min. The clear supernatant is removed and
recentrifuged at 165,000.times.g for 30 min. The resulting pellet
containing the oxytocin receptors is resuspended in 50.0 mM Tris.HCl
containing 5.0 mM MgCl.sub.2 at pH 7.4, to give a protein concentration of
2.5 mg/ml of tissue suspension. This preparation is used in subsequent
binding assays with ›.sup.3 H!Oxytocin.
Radioligand Binding
Binding of 3,5-›.sup.3 H!Oxytocin (›.sup.3 H!OT) to its receptors is done
in microtiter plates using ›.sup.3 H!OT, at various concentrations, in an
assay buffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl.sub.2,
and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg;
1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml
of buffer solution. Non-specific binding is determined in the presence of
1.0 uM unlabeled OT. The binding reaction is terminated after 60 min., at
22.degree. C., by rapid filtration through glass fiber filters using a
Brandel.RTM. cell harvester (Biomedical Research and Development
Laboratories, Inc., Gaithersburg, Md.). Competition experiments are
conducted at equilibrium using 1.0 nM ›.sup.3 H!OT and varying the
concentration of the displacing agents. The concentrations of agent
displacing 50% of ›.sup.3 H!OT at its sites (IC.sub.50) are calculated by
a computer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, U.S.A.).
The results of this assay on representative examples are shown in Table 3.
TABLE 3
______________________________________
Oxytocin Binding Assay
% Inhibition
Ex. No. Dose (.mu.M) at 10 .mu.M
IC.sub.50 (.mu.M)
______________________________________
361 10 57 6.4
5 10 47
6 10 94 1.7
7 10 65
1 10 93 2.5
2 10 91 1.3
3 1 21
4 1 0
16 1 23
364 1 30
365 10 57 2.5
367 10 63 2.1
______________________________________
The compounds of the present invention can be used in the form of salts
derived from pharmaceutically or physiologically acceptable acids or
bases. These salts include, but are not limited to, the following: salts
with inorganic acids such as hydrochloric acid, sulfuric acid, nitric
acid, phosphoric acid and, as the case may be, such organic acids as
acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts
include salts with alkali metals or alkaline earth metals, such as sodium,
potassium, calcium or magnesium or with organic bases. The compounds can
also be used in the form of esters, carbamates and other conventional
"pro-drug" forms, which, when administered in such form, convert to the
active moiety in vivo.
When the compounds are employed for the above utilities, they may be
combined with one or more pharmaceutically acceptable carriers, for
example, solvents, diluents and the like, and may be administered orally
in such forms as tablets, capsules, dispersible powders, granules, or
suspensions containing, for example, from about 0.05 to 5% of suspending
agent, syrups containing, for example, from about 10 to 50% of sugar, and
elixirs containing, for example, from about 20 to 50% ethanol, and the
like, or parenterally in the form of sterile injectable solutions or
suspensions containing from about 0.05 to 5% suspending agent in an
isotonic medium. Such pharmaceutical preparations may contain, for
example, from about 25 to about 90% of the active ingredient in
combination with the carrier, more usually between about 5% and 60% by
weight.
The effective dosage of active ingredient employed may vary depending on
the particular compound employed, the mode of administration and the
severity of the condition being treated. However, in general, satisfactory
results are obtained when the compounds of the invention are administered
at a daily dosage of from about 0.5 to about 500 mg/kg of animal body
weight, preferably given in divided doses two to four times a day, or in a
sustained release form. For most large mammals the total daily dosage is
from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms
suitable for internal use comprise from about 0.5 to 500 mg of the active
compound in intimate admixture with a solid or liquid pharmaceutically
acceptable carrier. This dosage regimen may be adjusted to provide the
optimal therapeutic response. For example, several divided doses may be
administered daily or the dose may be proportionally reduced as indicated
by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by
intravenous, intramuscular, or subcutaneous routes. Solid carriers include
starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose
and kaolin, while liquid carriers include sterile water, polyethylene
glycols, non-ionic surfactants and edible oils such as corn, peanut and
sesame oils, as are appropriate to the nature of the active ingredient and
the particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E, ascorbic
acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of
preparation and administration are solid compositions, particularly
tablets and hard-filled or liquid-filled capsules. Oral administration of
the compounds is preferred.
These active compounds may also be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a
free base or pharmacologically acceptable salt can be prepared in water
suitably mixed with a surfactant such as hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid, polyethylene glycols
and mixtures thereof in oils. Under ordinary conditions of storage and
use, these preparations contain a preservative to prevent the growth of
microorganisms.
The pharmaceutical forms suitable for injectable use include sterile
aqueous solutions or dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions or dispersions.
In all cases, the form must be sterile and must be fluid to the extent
that easy syringability exits. It must be stable under conditions of
manufacture and storage and must be preserved against the contaminating
action of microorganisms such as bacterial and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water, ethanol
(e.g., glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oil.
The new tricyclic non-peptide vasopressin antagonists of this invention are
useful in treating conditions where decreased vasopressin levels are
desired, such as in congestive heart failure, in disease conditions with
excess renal water reabsorption and in conditions with increased vascular
resistance and coronary vasoconstriction.
In particular, the vasopressin antagonists of this invention are
therapeutically useful in the treatment and/or prevention of hypertension,
cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal
vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome,
brain edema, cerebral ischemia, cerebral hemorrhage-stroke,
thrombosis-bleeding and abnormal states of water retention.
In particular, the oxytocin antagonists of this invention are useful in the
prevention of preterm labor and premature birth which is a significant
cause of infant health problems and infant mortality.
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